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'''Myalgic Encephalomyelitis''' (ME) is a chronic, [[inflammatory]], primarily [[neurological]] disease that is multi-systemic. Frequently triggered by a viral infection, it affects the [[central nervous system]] (CNS), [[immune system]], [[cardiovascular system]], [[endocrine system]], and [[musculoskeletal system]].<ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref><ref>[http://paradigmchange.me/wp-content/uploads/2016/04/ME-CFS-Medical-Abormalities-040416.pdf Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) Medical Abnormalities Research Citations Compiled by Lisa Petrison, Ph.D.Updated April 4, 2016 - PDF]</ref> It has been classified by the [[World Health Organization]] (WHO) as a neurological disease since 1969<ref>[https://en.wikipedia.org/wiki/History_of_chronic_fatigue_syndrome#International_classifications History of chronic fatigue syndrome - International Classifications]</ref><ref>[http://www.name-us.org/DefintionsPages/DefinitionsArticles/Hoopersdescription.pdf The Terminology of ME & CFS By Professor Malcolm Hooper - PDF]</ref> and has occurred in both [[Epidemic myalgic encephalomyelitis|epidemic]] and sporadic form since at least the 1930s, although is probably much older.


Myalgic Encephalomyelitis (ME) is a chronic, [[inflammatory]], post-viral, primarily [[neurological]] disease that is multisystemic, i.e. affecting the [[central nervous system]] (CNS), [[immune system]], [[cardiovascular system]], endocrinological system, and [[musculoskeletal system]].<ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref><ref>[http://paradigmchange.me/wp-content/uploads/2016/04/ME-CFS-Medical-Abormalities-040416.pdf Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) Medical Abnormalities Research Citations Compiled by Lisa Petrison, Ph.D.Updated April 4, 2016 - PDF]</ref> It has been classified by the ''World Health Organization'' (WHO) as a neurological disease since 1969.<ref>[https://en.wikipedia.org/wiki/History_of_chronic_fatigue_syndrome#International_classifications History of chronic fatigue syndrome - International Classifications]</ref><ref>[http://www.name-us.org/DefintionsPages/DefinitionsArticles/Hoopersdescription.pdf The Terminology of ME & CFS By Professor Malcolm Hooper - PDF]</ref> An ''M.E. Support'' article [http://www.mesupport.co.uk/index.php?page=the-symptoms-of-m-e#Cardinal-Symptoms The Symptoms of Myalgic Encephalomyelitis] has the headings: ''Cardinal Symptoms'', ''Secondary Features'', and ''Characterised Symptoms''. A list of symptoms can be found at [[The Hummingbirds' Foundation for ME]] article ''Myalgic Encephalomyelitis: The medical facts'' under the heading [http://www.hfme.org/methemedicalfacts.htm What are some of the symptoms of Myalgic Encephalomyelitis?]
A hallmark symptom of ME, [[Post-exertional malaise]], an intolerance to previously trivial cognitive or physical effort.<ref name=":0">[https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs ME/CFS - Pathways to Prevention - NIH]</ref><ref name=":1">[http://www.meactionuk.org.uk/definition.html Research Descriptions of M.E. - ME Action UK]</ref><ref name=":2">[http://www.cfids-me.org/ramsay86.html The Clinical Features of Myalgic Encephalomyelitis Melvin Ramsay, M.D., 1986]</ref><ref name=":3">[https://www.verywell.com/what-is-post-exertional-malaise-716023 What Is Post-exertional Malaise - Very Well - Adrienne Dellwo]</ref><ref name=":4">[https://www.verywell.com/post-exertional-malaise-715670 Post Exertional Malaise - Very Well - Adrienne Dellwo]</ref><ref name=":5">[http://www.webmd.com/chronic-fatigue-syndrome/chronic-fatigue-syndrome-symptoms Chronic Fatigue Syndrome - Web MD]</ref><ref name=":6">[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf PEM Series - Solve ME/CFS - Jenny Spotila]</ref> Other key symptoms include [[muscle]] [[Muscle weakness|weakness]] and [[Muscle fatigability|fatiguability]], sleep disturbance, and [[cognitive dysfunction]]. [[Autonomic nervous system]] dysfunction is frequent, although specific symptoms vary from patient to patient and may include [[Postural orthostatic tachycardia syndrome|postural orthostatic tachycardia]], [[Orthostatic intolerance|orthostatic hypotension]], cold intolerance and heat intolerance. Other common symptoms include muscle pain, neuropathic pain, neck and spine stiffness, and sensory symptoms including sensitivity to light, sound, touch, [[Paresthesia|paraesthesia]] and hyperaesthesia.


A hallmark symptom of ME, [[Post-exertional malaise]], is intolerance to previously trivial effort such as walking to the mailbox, running an errand or grocery shopping, taking a shower or brushing teeth, and deterioration of health from persistent or repeated exertion.<ref>[https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs ME/CFS - Pathways to Prevention - NIH]</ref><ref>[http://www.meactionuk.org.uk/definition.html Research Descriptions of M.E. - ME Action UK]</ref><ref>[http://www.cfids-me.org/ramsay86.html The Clinical Features of Myalgic Encephalomyelitis Melvin Ramsay, M.D., 1986]</ref><ref>[https://www.verywell.com/what-is-post-exertional-malaise-716023 What Is Post-exertional Malaise - Very Well - Adrienne Dellwo]</ref><ref>[https://www.verywell.com/post-exertional-malaise-715670 Post Exertional Malaise - Very Well - Adrienne Dellwo]</ref><ref>[http://www.webmd.com/chronic-fatigue-syndrome/chronic-fatigue-syndrome-symptoms Chronic Fatigue Syndrome - Web MD]</ref><ref>[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf PEM Series - Solve ME/CFS - Jenny Spotila]</ref> Myalgic encephalomyelitis is usually a relapsing-remitting disease with new symptoms occurring either in discrete relapses (or “crashes”) or accruing over time.<ref>[http://www.medscape.com/viewarticle/871482 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome - MedScape]</ref> The ''National Organization for Rare Disorders'' (NORD) notes that "Symptoms and their severity can fluctuate over the course of the illness, even from hour to hour."<ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref> The [[NIH]] notes that sensitivity to noise, light and chemichals may force patients to withdrawal from society.<ref>[https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs ME/CFS - Pathways to Prevention - Advancing the Research on Myalgic encephalomyelitis/Chronic Fatigue Syndrome]</ref>
Among adults, ME is more common in women than men. New onset has been observed in children as young as eight and in adults as old as eighty. Its course is usually relapsing-remitting with new symptoms occurring either in discrete relapses (or “crashes”) or accruing over time.<ref>[http://www.medscape.com/viewarticle/871482 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome - MedScape]</ref> There is a progressive form of ME but it is rarer than the relapsing-remitting type.<ref>[http://www.meassociation.org.uk/wp-content/uploads/fulltext_pmr-v2-id10521.pdf Progressive Myalgic Encephalomyelitis (ME) or A New Disease? A Case Report]</ref>  


ME does not have a cure, though treatments including the antiviral [[Ampligen]] (now approved for use on [[ME/CFS]] patients in [[Argentina]]) and immune system modulator [[Rituximab]] are being trialled.<ref>[http://www.prohealth.com/me-cfs/me-chronic-fatigue-syndrome-experimental-treatments.cfm Chronic Fatigue Syndrome & Myalgic Encephalomyelitis Experimental Treatments - ProHealth (Ampligen and Rituximab Tabs]</ref> There is a progressive form of ME but it is rarer than the relapsing-remitting type.<ref>[http://www.meassociation.org.uk/wp-content/uploads/fulltext_pmr-v2-id10521.pdf Progressive Myalgic Encephalomyelitis (ME) or A New Disease? A Case Report]</ref>
There are no approved treatments for ME in any country except for Argentina, which has approved [[Ampligen]] for the treatment of [[chronic fatigue syndrome]].


A [[CFS/ME]] Norwegian study shows the disease affects all ages, with two peak ages of 10-19 years and 30-39 years; it is more common in women than in men.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0167-5 Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine]</ref>  Research by the [[Open Medicine Foundation]] in its paper [[Metabolic features of chronic fatigue syndrome]] which studied severe [[CFS]] found that the disease is different in men and women but this is not related to testosterone or estrogen. [[Michael VanElzakker]] notes there are [http://me-pedia.org/wiki/Michael_VanElzakker#Male_and_female_differences_in_neuropathic_pain male and female differences in neuropathic pain]. "Younger children had a more equal gender balance compared to adolescents and adults."<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26510728 Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed]</ref>
== History ==


There is a controversial view that ME is not a chronic infectious or autoimmune disease, but rather a psychosocial illness triggered by infection or stress and noting a "high attack rate in females compared with males".<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700894/ Royal Free Epidemic of 1955: A Reconsideration - McEvedy and Beard - NCBI NLM NIH - PMC]</ref>. The [[BPS model]] is being applied to ME, CFS [[PVFS]] by psychiatrists in the UK.
{{Main article | History of myalgic encephalomyelitis and chronic fatigue syndrome}}


ME and CFS patients are barred from donating blood or organs in the [[United Kingdom]], [[United States]] and [[New Zealand]] while symptoms persist.<ref>[http://www.meassociation.org.uk/2010/08/people-with-mecfs-to-be-permanently-excluded-from-giving-blood-in-the-uk-from-1-november-this-year-department-of-health-announcement/ People with ME/CFS to be permanently excluded from giving blood in the UK from 1 November this year – Department of Health announcement - ME Association]</ref><ref>[http://www.redcrossblood.org/news/northcentral/american-red-cross-statement-xmrv-and-chronic-fatigue-syndrome American Red Cross Statement on XMRV and Chronic Fatigue Syndrome - American Red Cross]</ref><ref>[http://www.washingtonpost.com/wp-dyn/content/article/2010/12/03/AR2010120305888.html Chronic fatigue patients barred from blood donation - Washington Post -  By: Rob Stein - Dec 3, 2010]</ref><ref>[http://www.nzblood.co.nz/Give-blood/Donating/Detailed-eligibility-criteria#C - NZBlood]</ref>
ME has occurred in both [[Epidemic myalgic encephalomyelitis|epidemic]] and sporadic form since at least the 1930s, although is probably much older. The first recorded outbreak of epidemic myalgic encephalomyelitis was in [[1934 Los Angeles atypical polio outbreak|1934 in Los Angeles]] and was thought to be an outbreak of atypical polio. After the outbreak in [[Akureyri]], Iceland in 1946, the disease came to be called "Akureyri Disease" or [[Icelandic disease]] through much of the 1940s and 1950s. It was named [[Myalgic Encephalomyelitis|myalgic encephalomyelitis]] after London's [[Royal Free Hospital outbreak]] in 1955. Other names included benign myalgic encephalomyelitis and epidemic neuromyasthenia.


==Name describes disease==
After the [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]] outbreak in Nevada in 1984, the disease came to be called and redefined as [[Chronic Fatigue Syndrome]]. The most recent was putative outbreak was in Arizona in 1996. 
The name Myalgic Encephalomyelitis describes the disease: Myalgic (muscle pain), Encephalo (brain), myel (spinal cord), itis (inflammation).<ref>[http://www.name-us.org/DefintionsPages/DefinitionsArticles/Hoopersdescription.pdf The Terminology of ME & CFS By Professor Malcolm Hooper]</ref> The patient has muscle pain and the brain and spinal cord are inflamed.  


Dr. [[Melvin Ramsay]] used the term ME<ref>[http://www.name-us.org/DefintionsPages/DefinitionsArticles/Hoopersdescription.pdf The Terminology of ME & CFS By Professor Malcolm Hooper]</ref> which is now proving accurate due to brain fMRI's that detail the inflammation. The ''NY Times'' article [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder]] by [[David Tuller]] has brain images of a patient diagnosed with [[ME/CFS]] that clearly indicate brain inflammation. Other [http://me-pedia.org/wiki/Brain_imaging#Research brain imaging research] has been completed. Michael VanElzakker proposed the [[Vagus nerve infection hypothesis]].
==Disease name==


A survey by [[The MEAction Network]] in 2016 found patients much preferred the name myalgic encephalomyelitis to other names including [[Chronic Fatigue Syndrome]].<ref>[http://www.meaction.net/2016/08/07/meaction-rfi-poll-report-1-of-3/ MEAction RFI Poll Report (Part 1 of 3)]</ref>
{{Main article | Names of myalgic encephalomyelitis and chronic fatigue syndrome}}


The name myalgic encephalomyelitis was coined by Dr. [[Melvin Ramsay]] following the [[1955 Royal Free Hospital outbreak]]<ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1962472/ An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955 - The Medical Staff Of The Royal Free Hospital]</ref> and is a portmanteau of several of the key signs and symptoms of the disease: myalgic ([[muscle pain]]), encephalo ([[brain]]), myel ([[spinal cord]]), itis ([[inflammation]]).<ref>[http://www.name-us.org/DefintionsPages/DefinitionsArticles/Hoopersdescription.pdf The Terminology of ME & CFS By Professor Malcolm Hooper]</ref> 
Several other names have been used or proposed throughout the history of the disease, including [[atypical polio]], [[Icelandic disease]], benign myalgic encephalomyelitis, [[epidemic neuromyasthenia]], [[chronic fatigue syndrome]], and [[systemic exertion intolerance disease]]. This has lead to much confusion as a variety of names have been used at different times to describe discrete outbreaks as well as a larger and potentially more heterogenous population of sporadic cases, defined by a wide variety of [[Definitions of myalgic encephalomyelitis and chronic fatigue syndrome|case definitions]].
A survey by [[The MEAction Network]] in 2016 found that the majority of patients prefer the name myalgic encephalomyelitis to other names including [[Chronic Fatigue Syndrome|chronic fatigue syndrome]].<ref>[http://www.meaction.net/2016/08/07/meaction-rfi-poll-report-1-of-3/ MEAction RFI Poll Report (Part 1 of 3)]</ref> Most government agencies and researchers around the world use the term [[ME/CFS]].{{Citation needed}}
== Onset ==
Following after an incubation period of 4 to 7 days, the prodromal phase generally involve a flu-like illness with low-grade fever. In the majority but not all cases, an infection or infectious process is evident."<ref>[http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf ME Definition - Nightingale - PDF pg. 6]</ref> Two to seven days later, a chronic phase commences, characterized by a measurable diffuse change in the function of the [[central nervous system]]. It is this second phase, persistent phase that most M.E."<ref>[http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf ME Definition - Nightingale - PDF pg. 6]</ref>
In some patients, the initial presentation involved a severe, incapacitating prolonged illness. In others, an apparent remission was followed by relapses brought on by exertion, [[menstrual period]], or cold.
==Signs and symptoms==
==Signs and symptoms==
Over-exertion can make ME worse and the effects are often delayed and may not be seen within 24 hours.<ref>[http://www.investinme.org/landerP5.shtml What is ME - Invest in ME Research]</ref> <ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref>


[[Invest in ME]] outlines [[ME]] symptoms and notes symptoms can range from mild to very severe and can include:
Symptoms can range from mild to very severe and can include:


<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">


*Reaction to physical and mental activity and sensory input
*low-grade fever, temperature instability
*Cardiovascular and [[Cardiac problems]]
*[[post-exertional malaise]]  
*[[Cognitive dysfunction]]
*[[Cognitive dysfunction]]
*[[Gastrointestinal system]] Problems
*[[muscle]] [[Muscle weakness|weakness]] and [[Muscle fatigability|fatiguability]]
*[[Headache]]
*[[Headache]]
*Hormonal Imbalance
*[[myalgia]]
*Immunological Problems
*[[neuralgia]]
*[[Muscle fatigability]] and Intense Pain
*[[ataxia]]
*Neurological Problems
*[[gastrointestinal]] symptoms
*Sleep Problems ([[Sleep dysfunction]])
*[[sleep dysfunction]]
*neck and back or spinal cord stiffness
*sensitivity to light, sound and/or touch
*sensitivity to heat or cold


</div>
</div>
 
Symptoms presentation and severity can vary considerably day to day and even hour to hour.<ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref> Overexertion can make all symptoms worse, the effects are often delayed and may not be seen within 24 hours.<ref>[http://www.investinme.org/landerP5.shtml What is ME - Invest in ME Research]</ref> <ref>[https://rarediseases.org/rare-diseases/myalgic-encephalomyelitis/ Myalgic Encephalomyelitis - NORD]</ref> The US [[National Institutes of Health]] notes that sensitivity to noise, light and chemicals may force patients to withdraw from society.<ref>[https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs ME/CFS - Pathways to Prevention - Advancing the Research on Myalgic encephalomyelitis/Chronic Fatigue Syndrome]</ref>
 
=== Post-exertional malaise ===
=== Post-exertional malaise ===
A core symptom, [[Post-exertional malaise]], is used in diagnosing [[ME]], [[CFS]], [[ME/CFS]] and [[SEID]].
{{Main article | Post-exertional malaise}}
A core symptom, [[Post-exertional malaise]], is intolerance to previously trivial effort such as walking to the mailbox, running an errand or grocery shopping, taking a shower or brushing teeth, and deterioration of health from persistent or repeated exertion.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" /><ref name=":6" />
 
== Clinical findings ==
Although there is no definitive [[biomarker]], several signs and findings have been frequently observed in clinical settings:<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
 
*Reaction to physical and mental activity and sensory input
*[[Postural orthostatic tachycardia syndrome|postural orthostatic tachychardia]]
*[[Hormones|hormone]] imbalance
*[[Immune system|Immunological abnormalities]]
*[[Natural Killer Cell (NKC) function|low natural killer cell function]]
*high titers to specific infection
*low red blood cell [[magnesium]]


</div>
==Diagnosis==
==Diagnosis==
The [[International Consensus Criteria]] (ICC) is thought to be the best tool for diagnosing [[ME]] while the [[Canadian Consensus Criteria]] (CCC)  diagnoses both ME and [[Chronic Fatigue Syndrome]] (CFS) and is an [[ME/CFS]] diagnostic tool.


The original criteria developed by [[Melvin Ramsay]], the [[Ramsay definition]], is not used for diagnosing ME today.
{{Main article | Definitions of myalgic encephalomyelitis and chronic fatigue syndrome}}
 
There are several proposed criteria for diagnosing ME including the [[International Consensus Criteria]] (ICC) and the [[Canadian Consensus Criteria]] (CCC). The original criteria developed by [[Melvin Ramsay]], the [[Ramsay definition]], is not used for diagnosing ME today.


=== Other diagnostic criteria ===
=== Other diagnostic criteria ===
The UK [[Oxford criteria]] (the US [[Institute of Medicine report]] has called for its retirement)<ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped]</ref> and the US CDC [[Fukuda criteria]] (used in some research worldwide) are not describing ME but instead describe [[Chronic fatigue]] (CF). CF should not be confused with [[CFS]]. Many patients and ME organizations believe CFS must not be confused with ME nor its diagnostic criteria used to describe, diagnose or research ME.
Several, overly broad criteria have been proposed and are in use. These criteria likely capture some patients with the disease characterized in the medical literature on [[Epidemic myalgic encephalomyelitis|epidemic ME]], exclude others, and also include patients with a wide range of other undiagnosed conditions including cancer, depression, and a range of autoimmune diseases. The United Kingdom's [[Oxford criteria]] is the broadest and likely most heterogenous definition. (The US [[Institute of Medicine report]] called for its complete retirement<ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped]</ref>). The US [[Centers for Disease Control and Prevention|Centers for Disease Control]]'s [[Fukuda criteria]], in use since 1994, is also overly broad.


===Differential diagnosis===
===Differential diagnosis===
The signs and symptoms of ME can be similar to other medical problems, "such as cancer, [[multiple sclerosis]], lupus, [[brucellosis]], or another condition."<ref>[https://www.dartmouth-hitchcock.org/medical-information/health_encyclopedia/nord792 Dartmouth Hitchock - Myalgic Encephalomyelitis National Organization for Rare Disorders, Inc.]</ref> Additional testing may be needed to help distinguish ME from these other problems.
The signs and symptoms of ME can be similar to other medical problems, "such as cancer, [[multiple sclerosis]], lupus, [[brucellosis]], or another condition."<ref>[https://www.dartmouth-hitchcock.org/medical-information/health_encyclopedia/nord792 Dartmouth Hitchock - Myalgic Encephalomyelitis National Organization for Rare Disorders, Inc.]</ref> Additional testing may be needed to help distinguish ME from these other problems.


==Disease course and clinical subtypes==
== Course & Prognosis ==
'''Primary Phase'''
ME relapses are often a result of over-activity, but can occur without warning with no obvious inciting factors. Exposure to increased sensory information in light, sound, and movement can provoke a sensory storm.


"The first phase is an epidemic or endemic (sporadic) infectious disease generally with an incubation period of 4 to 7 days; in most, but not all cases, an infection or infectious process is evident."<ref>[http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf ME Definition - Nightingale - PDF pg. 6]</ref>
Infections, such as the common cold, influenza and gastroenteritis, also increase the risk for a relapse. Heat and cold can transiently increase symptoms.


'''Secondary Chronic Phase'''
Pregnancy can directly affect the susceptibility for relapse. Later pregnancy appears to offer a natural protection against relapses, and there are anecdotal reports of postpartum remission. However, pregnancy does not seem to influence long-term disability.
 
"The second and chronic phase follows closely on the first phase, usually within two to seven days; it is
characterized by a measurable diffuse change in the function of the Central Nervous System. This
second phase is the persisting disease that most characterizes M.E."<ref>[http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf ME Definition - Nightingale - PDF pg. 6]</ref>
 
"The initial presentation takes one of two forms: a severe, incapacitating prolonged illness, or an apparent remission followed by increasing relapses until the patient is forced to recognise exertional limitation. The most common initial symptoms reported are: Pain in the spine, neck or head; mild fever and flu-like symptoms; nausea or vomiting; flaccid muscle weakness; and muscle pain or tenderness."<ref>[https://arainbowatnight.com/whatisme/ https://arainbowatnight.com/whatisme/ What Is ME? - Disease course and clinical subtypes - A rainbow at night]</ref> For some people, ME is triggered by Hepatitis B vaccination <ref>[http://www.meassociation.org.uk/2016/01/were-collecting-information-on-hepatitis-b-vaccination-and-mecfs-can-you-help-13-january-2016/ ME Association Survey Report, 2010]</ref>, blood transfusion<ref>[https://www.masscfids.org/resource-library/3-research/119-can-blood-transfusions-cause-cfids- Can Blood Transfusions Cause ME/CFS? - Massachusetts CFIDS/ME & FM Association]</ref>, or chemical poisoning<ref>[http://www.prohealth.com/library/showarticle.cfm?libid=8267 Tired or Toxic? Chronic Fatigue Syndrome and Environmental Toxicity - Michael A. Schmidt - ProHealth]</ref><ref>[http://drmyhill.co.uk/wiki/Toxic_causes_of_CFS_-_the_more_I_ask,_the_more_I_find! Toxic causes of CFS - the more I ask, the more I find! - Dr. Myhill.co.uk]</ref> (See: [[Countess of Mar]]), although it is now thought organophosphate poisoning is a different illness.<ref>[http://apt.rcpsych.org/content/aptrcpsych/6/3/187.full.pdf Chronic exposure to organophosphates: background and clinical picture - Robert Davies, Ghouse Ahmed & Tegwedd Freer]</ref><ref>[https://arainbowatnight.com/whatisme/ https://arainbowatnight.com/whatisme/ What Is ME? - Disease course and clinical subtypes - A rainbow at night]</ref>


"The later course of ME. is difficult to predict, and may either become consistently severe, improve to a plateau, or be markedly relapse-remitting. In some, even prolonged severe incapacitation can be relieved by unpredictable remission, although relapse is always possible. The degree of impairment and complexity depends on the degree of diffuse brain injury and end organ involvement.
"The later course of ME. is difficult to predict, and may either become consistently severe, improve to a plateau, or be markedly relapse-remitting. In some, even prolonged severe incapacitation can be relieved by unpredictable remission, although relapse is always possible. The degree of impairment and complexity depends on the degree of diffuse brain injury and end organ involvement."<ref>[https://arainbowatnight.com/whatisme/#Signs_and_symptoms What Is ME? - Disease course and clinical subtypes - A rainbow at night]</ref>


The evidence for subgroups is strengthened by research using heterogeneous CFS criteria, although this artificial heterogeneity also hampers consensus. It is likely that subtypes exist within the ME milieu based on the clinical findings, history, and perhaps gender of patients."<ref>[https://arainbowatnight.com/whatisme/#Signs_and_symptoms What Is ME? - Disease course and clinical subtypes - A rainbow at night]</ref>
==Clinical subtypes==
There are no standard subtypes. Some researchers and clinicians have proposed distinguishing between a relapsing-remitting and progressive course.{{Citation needed}} However, it is difficult to distinguish between natural variation in the population of ME patients who might share a common disease process but owing to individual, genetic, or environmental differences, have different symptom clusters or disease course versus heterogeneity created by imprecise criteria and misdiagnosis.<ref>[https://arainbowatnight.com/whatisme/#Signs_and_symptoms What Is ME? - Disease course and clinical subtypes - A rainbow at night]</ref>


=== Subtypes proposed ===
Kerr et al proposed 7 different subsets for “CFS” as it is defined today:<ref>[http://me-ireland.com/genes2.pdf Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes - JCP Online]</ref>
Kerr et al proposed 7 different subsets for “CFS” as it is defined today:<ref>[http://me-ireland.com/genes2.pdf Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes - JCP Online]</ref>


Line 88: Line 109:
* Subtype 7 This is one of the more severe subtypes. Effects are pain, infections, musculoskeletal, sleep-related, neurological, gastrointestinal, neurocognitive and anxiety/depression.
* Subtype 7 This is one of the more severe subtypes. Effects are pain, infections, musculoskeletal, sleep-related, neurological, gastrointestinal, neurocognitive and anxiety/depression.


==Severity==
==Pathophysiology==
ME is a multi-system disease. Numerous biological abnormalities have been found in multiple bodily system, however no common, central cause or mechanism has yet been elucidated.
 
=== Central nervous system ===
{{Main article |Central nervous system}}Radiological research on ME has shown hypoperfusion of the brain stem and an abnormal response to exertion, but research on CFS is often inconsistent and must be interpreted with caution. For example, a reduced volume of grey matter may be a result of a lack of activity and is reversible with cognitive behavior therapy.


===Factors triggering a relapse===
=== Autonomic nervous system ===
{{Main article |Autonomic nervous system}}


ME relapses are often a result of over-activity, but can occur without warning with no obvious inciting factors. Exposure to increased sensory information in light, sound, and movement can provoke a sensory storm.  
=== Peripheral nervous system ===
{{Main article |Muscle}}An inquest into the death of [[Sophia Mirza]] from ME found inflammation of the dorsal spine ganglia and liver abnormalities.
 
=== Musculoskeletal system ===
{{Main article |Muscle}}
 
=== Immune system ===
{{Main article |Immune system}}
 
According to a strictly immunological explanation of CFS, the inflammatory processes triggered by [[T cell]]s create leaks in the [[blood-brain barrier]] (a capillary system that should prevent entrance of T-cells in the nervous system). These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of [[cytokine]]s and other destructive proteins such as [[RNase L|Rnase-L]]. [[Channelopathy]], a reduced ability to move metabolites in and out of cells has been implicated in this process. This may also be applicable to ME.
 
=== Chronic infection ===
Some evidence shows viral infection of muscle and brain in at least a proportion of sufferers. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. A model for late ME has been proposed analogously to post-polio syndrome in which repaired nerve tissue forms inappropriately [The Late Effects of ME: Can they be distinguished from the Post-polio syndrome?].  


Infections, such as the common cold, influenza and gastroenteritis, also increase the risk for a relapse. Heat and cold can transiently increase symptoms.
=== Cardiovascular ===
Hemodynamic abnormalities are widely found, including serum and RBC hypovolemia, NMH, and cerebral hypoperfusion. Vascular and endothelial abnormalities have been published by MERUK. However, none of these studies used research criteria for ME so the results may not be applicable to ME.


Pregnancy can directly affect the susceptibility for relapse. Later pregnancy appears to offer a natural protection against relapses, and there are anecdotal reports of postpartum remission. However, pregnancy does not seem to influence long-term disability.
Some cardiologic features such as cardiac insufficiency, inverted T-waves and myofiber disarray have been reported in CFS and recently added to by findings of reduced Q-value. This has led clinician and researcher Dr. Paul Cheney to posit that CFS is form of partially compensated cardiomyopathy in which [[orthostatic intolerance]] and rapid fatiguability are secondary protective mechanisms. Due to the heterogeneity of the population, a single cause is unlikely, but one-third of people with ME have abnormalities when tested with Holter monitors.


==Pathophysiology==
=== Gastrointestinal system ===
{{Main article |Gastrointestinal system}}


Although much is known about abnormalities in ME., the reasons why they occur is not known. There are two ME. conferences held in the UK each year attended by international research luminaries, and other conferences held worldwide.
== Sex differences ==
{{Main article | Sex differences in myalgic encephalomyelitis and chronic fatigue syndrome}}
A [[CFS/ME]] Norwegian study shows the disease affects all ages, with two peak ages of 10-19 years and 30-39 years; it is more common in women than in men.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0167-5 Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine]</ref>  Research by the [[Open Medicine Foundation]] cited in its paper, [[Metabolic features of chronic fatigue syndrome]] which studied severe [[CFS]], found that the disease is different in men and women but this is not related to testosterone or estrogen. [[Michael VanElzakker]] notes there are [http://me-pedia.org/wiki/Michael_VanElzakker#Male_and_female_differences_in_neuropathic_pain male and female differences in neuropathic pain]. A study of UK and Dutch co-horts found "younger children had a more equal gender balance compared to adolescents and adults."<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26510728 Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed]</ref>


ME is a complex disease in which the immune and neurological systems appear dysregulated and in conflict, producing a wide variety of findings.
==Risk factors and potential causes==


The problem is that most of the research in recent years has been conducted on people with CFS. This is a heterogeneous population, and includes patients with psychiatric disorders, as well as vitamin and nutritional deficiencies (especially vitamin D) and post-viral states such as ME.
{{Main article | Risk factors and potential causes of myalgic encephalomyelitis and chronic fatigue syndrome}}


According to a strictly immunological explanation of CFS, the inflammatory processes triggered by [[T cell]]s create leaks in the [[blood-brain barrier]] (a capillary system that should prevent entrance of T-cells in the nervous system). These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of [[cytokine]]s and other destructive proteins such as Rnase-L. A reduced ability to move metabolites in and out of cells (channelopathy) has been implicated in this process. This may also be applicable to ME.
===Risk factors===


Some evidence shows viral infection of muscle and brain in at least a proportion of sufferers. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. A model for late ME has been proposed analogously to post-polio syndrome in which repaired nerve tissue forms inappropriately [The Late Effects of ME: Can they be distinguished from the Post-polio syndrome?]. Radiological research on ME has shown hypoperfusion of the brain stem and an abnormal response to exertion, but research on CFS is often inconsistent and must be interpreted with caution. For example, a reduced volume of grey matter may be a result of a lack of activity and is reversible with cognitive behaviour therapy.
===Potential causes===


An inquest into the death of [[Sophia Mirza]] from ME found inflammation of the dorsal spine ganglia and liver abnormalities. However, she had co-morbid disorders.
Although risk factors for myalgic encephalomyelitis have been identified, no single definitive virus has been found in all cases, which has led to the claim that ME is a common end path of a variety of infectious insults.<ref>[http://via.library.depaul.edu/csh_etd/117/ Onset Patterns of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: A Mixed Method Approach - Meredyth Evans - DePaul University]</ref><ref>[http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis Vagus nerve infection hypothesis - MEpedia]</ref><ref>[http://www.clevelandclinicmeded.com/online/casebased/decisionmaking/chronic-fatigue/case3.htm Chronic Fatigue Syndrome - Cleveland Clinic]</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/26475444/ Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. - PubMed]</ref> It is still possible ME involves some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26604026 Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. RA Underhill - PubMed]</ref><ref>[http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome]</ref> Several theories suggest that ME is an inappropriate immune response to an infection, a theory bolstered by the observation that there is sometimes a family history of [[autoimmune disease]].<ref>[https://www.facebook.com/permalink.php?story_fbid=564532390371988&id=564526123705948 Klimas ME/CFS Genes Study - Face Book - Video]</ref> There is also a shift from the [[Th1]] type of helper [[T cell]]s, which fight infection, to the [[Th2]] type, which are more active in allergy and more likely to attack the body.<ref>[http://www.sciencedirect.com/science/article/pii/S1043466614006024 Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis - ScienceDirect]</ref><ref>[http://www.m-hikari.com/bmgt/bmgt2014/bmgt1-4-2014/hardcastleBMGT1-4-2014.pdf Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and the Potential Role of T Cells - Biological Markers and Guided Therapy, Vol. 1, 2014, no. 1, 25 -38 - PDF]</ref>


Hemodynamic abnormalities are widely found, including serum and RBC hypovolemia, NMH, cerebral hypoperfusion. Vascular and endothelial abnormalities have been published by MERUK. However, none of these studies used research criteria for ME so the results may not be applicable to ME.
===Viruses===


Some cardiological features such as cardiac insufficiency, inverted T-waves and myofiber disarray have been reported in CFS and recently added to by findings of reduced Q-value. This has led clinician and researcher Dr. Paul Cheney to posit that CFS is form of partially compensated cardiomyopathy in which [[orthostatic intolerance]] and rapid fatiguability are secondary protective mechanisms. Due to the heterogeneity of the population, a single cause is unlikely, but one-third of people with ME have abnormalities when tested with Holter monitors.
{{Main article | Viruses}}


==Causes==
Other theories describe ME as an immune response to a chronic infection. The association between ME and the [[Coxsackie B]], [[HHV-6]], and [[HHV-7]] viruses<ref>[https://www.ncbi.nlm.nih.gov/pubmed/2841461 Coxsackie B viruses and myalgic encephalomyelitis.]</ref><ref>[http://solvecfs.org/ramsay-research-team-5-the-potential-role-of-hhv-6-in-mecfs/ Ramsay Research Team 5 – The Potential Role of HHV-6 in ME/CFS]</ref> <ref>[https://www.ncbi.nlm.nih.gov/pubmed/22927850 Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome.]</ref> suggests a potential viral contribution in at least some individuals. Evidence from [[epidemic myalgic encephalomyelitis]] strongly point to an enterovirus, however, in most outbreaks, no virus was successfully isolated.


Although risk factors for myalgic encephalomyelitis have been identified, no single definitive virus has been found in all cases, which has led to the claim that ME is a common end path of a variety of infectious insults.<ref>[http://via.library.depaul.edu/csh_etd/117/ Onset Patterns of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: A Mixed Method Approach - Meredyth Evans - DePaul University]</ref><ref>[http://me-pedia.org/wiki/Vagus_nerve_infection_hypothesis Vagus nerve infection hypothesis - MEpedia]</ref><ref>[http://www.clevelandclinicmeded.com/online/casebased/decisionmaking/chronic-fatigue/case3.htm Chronic Fatigue Syndrome - Cleveland Clinic]</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/26475444/ Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. - PubMed]</ref> It is still possible ME involves some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26604026 Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. RA Underhill - PubMed]</ref><ref>[http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome]</ref> Although most accept an infectious explanation, several theories suggest that ME is an inappropriate immune response to an underlying condition, a theory bolstered by the observation that there is sometimes a family history of autoimmune disease.<ref>[https://www.facebook.com/permalink.php?story_fbid=564532390371988&id=564526123705948 Klimas ME/CFS Genes Study - Face Book - Video]</ref> There is also a shift from the [[Th1]] type of helper [[T cell]]s, which fight infection, to the [[Th2]] type, which are more active in allergy and more likely to attack the body.<ref>[http://www.sciencedirect.com/science/article/pii/S1043466614006024 Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis - ScienceDirect]</ref><ref>[http://www.m-hikari.com/bmgt/bmgt2014/bmgt1-4-2014/hardcastleBMGT1-4-2014.pdf Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and the Potential Role of T Cells - Biological Markers and Guided Therapy, Vol. 1, 2014, no. 1, 25 -38 - PDF]</ref>
=== Bacteria ===


===Environmental===
{{Main article | Bacteria}}


The most popular hypothesis is that a viral infection or retroviral reactivation primes a susceptible immune system for an abnormal reaction later in life. On a molecular level, this might occur if there is a structural similarity between the infectious virus and some component of the central nervous system, leading to eventual confusion in the immune system.
Others believe ME may sometimes result from a chronic infection with spirochetal bacteria, such as [[Lyme disease]]. Another bacterium that has been implicated in ME is [[Chlamydia pneumoniae]].<ref>[http://med.stanford.edu/chronicfatiguesyndrome/infections/chlamydia/chlamydia-experts.html Chlamydia Pneumoniae - Stanford Myalgic Encephalomyelitis/Chronic Fatigue syndrome Initiative]</ref> Protein findings relating to several infections have seen found in the oligoclonal bands ME patients.<ref>[http://www.nytimes.com/health/guides/test/csf-oligoclonal-banding/overview.html CSF Oligoclonal Banding - NY Times]</ref>


Since ME seems to be more common in people who live farther from the equator, another theory proposes that decreased sunlight exposure and possibly decreased [[vitamin D]] production may help cause ME. This theory is bolstered by recent research into the biochemistry of vitamin D, which has shown that it is an important immune system regulator.
The [[Vagus nerve infection hypothesis]] accounts for why so many different infectious onsets could be responsible. The Vagus nerve runs from the brain stem and throughout the body and has an impact on many body systems.


Other theories describe ME as an immune response to a chronic infection. The association between ME and the [[Coxsackie B]], [[HHV-6]], and [[HHV-7]] viruses suggests a potential viral contribution in at least some individuals. Others believe ME may sometimes result from a chronic infection with spirochetal bacteria, such as [[Lyme disease]]. Another bacterium that has been implicated in ME is [[Chlamydia pneumoniae]]. Protein findings relating to several infections have seen found in the oligoclonal bands ME patients. Research has shown that, much like the relationship between HIV and AIDS, the immune dysfunction accompanying ME can lead to temporary or permanent disease progression, regardless of the infection or combination of infections to which the ME sufferer is exposed. Additionally, ME sufferers can be more prone to opportunistic infections.
Given the uncertainty regarding the cause, ME and CFS patients are barred from donating blood or organs in the [[United Kingdom]], [[United States]] and [[New Zealand]] while symptoms persist.<ref>[http://www.meassociation.org.uk/2010/08/people-with-mecfs-to-be-permanently-excluded-from-giving-blood-in-the-uk-from-1-november-this-year-department-of-health-announcement/ People with ME/CFS to be permanently excluded from giving blood in the UK from 1 November this year – Department of Health announcement - ME Association]</ref><ref>[http://www.redcrossblood.org/news/northcentral/american-red-cross-statement-xmrv-and-chronic-fatigue-syndrome American Red Cross Statement on XMRV and Chronic Fatigue Syndrome - American Red Cross]</ref><ref>[http://www.washingtonpost.com/wp-dyn/content/article/2010/12/03/AR2010120305888.html Chronic fatigue patients barred from blood donation - Washington Post -  By: Rob Stein - Dec 3, 2010]</ref><ref>[http://www.nzblood.co.nz/Give-blood/Donating/Detailed-eligibility-criteria#C - NZBlood]</ref>


==Treatments==
==Treatments==
{{Main article | Potential treatments for myalgic encephalomyelitis and chronic fatigue syndrome}}
There is no known cure for ME. Treatments for sleep problems, headaches and pain are utilized by some doctors for some patients although these are treating symptoms and not ME itself. Success of treating symptoms of ME is not well researched or documented.
There is no known cure for ME. Treatments for sleep problems, headaches and pain are utilized by some doctors for some patients although these are treating symptoms and not ME itself. Success of treating symptoms of ME is not well researched or documented.


[[Ampligen]] (Approved for ME/CFS in [[Argentina]]) and [[Rituximab]] are being trialled.
[[Ampligen]] (Approved for ME/CFS in [[Argentina]]) and [[Rituximab]] are being trialled.
ME does not have a cure, though treatments including the antiviral [[Ampligen]] (now approved for use on [[ME/CFS]] patients in [[Argentina]]) and immune system modulator [[Rituximab]] are being trialled.<ref>[http://www.prohealth.com/me-cfs/me-chronic-fatigue-syndrome-experimental-treatments.cfm Chronic Fatigue Syndrome & Myalgic Encephalomyelitis Experimental Treatments - ProHealth (Ampligen and Rituximab Tabs]</ref>


==Epidemiology==
==Epidemiology==


ME has been found world-wide, in at least 63 epidemics documented in published papers from the 1930s to the 1980s.<ref>[http://www.hfme.org/methemedicalfacts.htm Myalgic Encephalomyelitis: The medical facts - What causes Myalgic Encephalomyelitis? Are there outbreaks of M.E.?]</ref> (See: [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks]].)  Epidemics often occur in enclosed communities such as schools and hospitals.
{{Main article | Epidemiology of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome}}
 
ME has been found world-wide, in at least 75 [[Outbreaks|epidemics]] documented in published papers from the 1930s to the 1980s.<ref>[http://www.hfme.org/methemedicalfacts.htm Myalgic Encephalomyelitis: The medical facts - What causes Myalgic Encephalomyelitis? Are there outbreaks of M.E.?]</ref> Epidemics often occur in enclosed communities such as schools and hospitals.


As observed in many autoimmune disorders, ME is more common in females than males; the mean sex ratio is approxmately 2-3 females for every male.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0167-5 Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine]</ref> In children the sex ratio is approximately equal.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26510728 Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed]</ref>
As observed in many autoimmune disorders, ME is more common in females than males; the mean sex ratio is approxmately 2-3 females for every male.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0167-5 Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine]</ref> In children the sex ratio is approximately equal.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/26510728 Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed]</ref>


== Co-morbidities ==
Clinicians have observed several predisposing conditions, co-morbidities, overlapping conditions, and increased risks for secondary diseases in patients with ME. However, as no large-scale epidemiological studies, genetic studies, or family studies have been done, there is little than can be said definitively about the rate or underlying biological reasons for potentially related conditions. Different case definitions and resulting misdiagnoses add to the confusion. Moreover, certain conditions such as [[postural orthostatic tachycardia syndrome]] (POTS) and [[idiopathic intracranial hypertension]] (IIH) are symptoms that can occur in numerous conditions, including ME. The following are some syndromes and diseases that have been associated with (or in some cases, misdiagnosed as) ME:
<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*[[fibromyalgia]]
*[[Chronic lyme disease|chronic Lyme disease]]
*[[Postural orthostatic tachycardia syndrome|postural orthostatic tachychardia syndrome]]
*[[mast cell activation disorder]]
*[[thyroid disease]]
*[[Ehlers-Danlos syndrome]]
*[[endometriosis]]
*[[Sjögren's syndrome]]
*[[mold illness]]
*[[multiple chemical sensitivity]]
*[[environmentally acquired illness]]
*[[chronic inflammatory response syndrome]]
*[[cancer]]
*[[idiopathic intracranial hypertension]]
</div>
== See also ==


*[[Pediatric|Pediatric myalgic encephalomyelitis]]


== References ==
== References ==
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[[Category:Diagnoses]]
[[Category:Diagnoses]]
[[Category:Disease names]]
[[Category:Disease names]]
<references />

Revision as of 16:01, July 13, 2018

Myalgic Encephalomyelitis (ME) is a chronic, inflammatory, primarily neurological disease that is multi-systemic. Frequently triggered by a viral infection, it affects the central nervous system (CNS), immune system, cardiovascular system, endocrine system, and musculoskeletal system.[1][2] It has been classified by the World Health Organization (WHO) as a neurological disease since 1969[3][4] and has occurred in both epidemic and sporadic form since at least the 1930s, although is probably much older.

A hallmark symptom of ME, Post-exertional malaise, an intolerance to previously trivial cognitive or physical effort.[5][6][7][8][9][10][11] Other key symptoms include muscle weakness and fatiguability, sleep disturbance, and cognitive dysfunction. Autonomic nervous system dysfunction is frequent, although specific symptoms vary from patient to patient and may include postural orthostatic tachycardia, orthostatic hypotension, cold intolerance and heat intolerance. Other common symptoms include muscle pain, neuropathic pain, neck and spine stiffness, and sensory symptoms including sensitivity to light, sound, touch, paraesthesia and hyperaesthesia.

Among adults, ME is more common in women than men. New onset has been observed in children as young as eight and in adults as old as eighty. Its course is usually relapsing-remitting with new symptoms occurring either in discrete relapses (or “crashes”) or accruing over time.[12] There is a progressive form of ME but it is rarer than the relapsing-remitting type.[13]

There are no approved treatments for ME in any country except for Argentina, which has approved Ampligen for the treatment of chronic fatigue syndrome.

History[edit | edit source]

ME has occurred in both epidemic and sporadic form since at least the 1930s, although is probably much older. The first recorded outbreak of epidemic myalgic encephalomyelitis was in 1934 in Los Angeles and was thought to be an outbreak of atypical polio. After the outbreak in Akureyri, Iceland in 1946, the disease came to be called "Akureyri Disease" or Icelandic disease through much of the 1940s and 1950s. It was named myalgic encephalomyelitis after London's Royal Free Hospital outbreak in 1955. Other names included benign myalgic encephalomyelitis and epidemic neuromyasthenia.

After the Incline Village outbreak in Nevada in 1984, the disease came to be called and redefined as Chronic Fatigue Syndrome. The most recent was putative outbreak was in Arizona in 1996. 

Disease name[edit | edit source]

The name myalgic encephalomyelitis was coined by Dr. Melvin Ramsay following the 1955 Royal Free Hospital outbreak[14] and is a portmanteau of several of the key signs and symptoms of the disease: myalgic (muscle pain), encephalo (brain), myel (spinal cord), itis (inflammation).[15]

Several other names have been used or proposed throughout the history of the disease, including atypical polio, Icelandic disease, benign myalgic encephalomyelitis, epidemic neuromyasthenia, chronic fatigue syndrome, and systemic exertion intolerance disease. This has lead to much confusion as a variety of names have been used at different times to describe discrete outbreaks as well as a larger and potentially more heterogenous population of sporadic cases, defined by a wide variety of case definitions.

A survey by The MEAction Network in 2016 found that the majority of patients prefer the name myalgic encephalomyelitis to other names including chronic fatigue syndrome.[16] Most government agencies and researchers around the world use the term ME/CFS.[citation needed]

Onset[edit | edit source]

Following after an incubation period of 4 to 7 days, the prodromal phase generally involve a flu-like illness with low-grade fever. In the majority but not all cases, an infection or infectious process is evident."[17] Two to seven days later, a chronic phase commences, characterized by a measurable diffuse change in the function of the central nervous system. It is this second phase, persistent phase that most M.E."[18]

In some patients, the initial presentation involved a severe, incapacitating prolonged illness. In others, an apparent remission was followed by relapses brought on by exertion, menstrual period, or cold.

Signs and symptoms[edit | edit source]

Symptoms can range from mild to very severe and can include:

Symptoms presentation and severity can vary considerably day to day and even hour to hour.[19] Overexertion can make all symptoms worse, the effects are often delayed and may not be seen within 24 hours.[20] [21] The US National Institutes of Health notes that sensitivity to noise, light and chemicals may force patients to withdraw from society.[22]

Post-exertional malaise[edit | edit source]

A core symptom, Post-exertional malaise, is intolerance to previously trivial effort such as walking to the mailbox, running an errand or grocery shopping, taking a shower or brushing teeth, and deterioration of health from persistent or repeated exertion.[5][6][7][8][9][10][11]

Clinical findings[edit | edit source]

Although there is no definitive biomarker, several signs and findings have been frequently observed in clinical settings:

Diagnosis[edit | edit source]

There are several proposed criteria for diagnosing ME including the International Consensus Criteria (ICC) and the Canadian Consensus Criteria (CCC). The original criteria developed by Melvin Ramsay, the Ramsay definition, is not used for diagnosing ME today.

Other diagnostic criteria[edit | edit source]

Several, overly broad criteria have been proposed and are in use. These criteria likely capture some patients with the disease characterized in the medical literature on epidemic ME, exclude others, and also include patients with a wide range of other undiagnosed conditions including cancer, depression, and a range of autoimmune diseases. The United Kingdom's Oxford criteria is the broadest and likely most heterogenous definition. (The US Institute of Medicine report called for its complete retirement[23]). The US Centers for Disease Control's Fukuda criteria, in use since 1994, is also overly broad.

Differential diagnosis[edit | edit source]

The signs and symptoms of ME can be similar to other medical problems, "such as cancer, multiple sclerosis, lupus, brucellosis, or another condition."[24] Additional testing may be needed to help distinguish ME from these other problems.

Course & Prognosis[edit | edit source]

ME relapses are often a result of over-activity, but can occur without warning with no obvious inciting factors. Exposure to increased sensory information in light, sound, and movement can provoke a sensory storm.

Infections, such as the common cold, influenza and gastroenteritis, also increase the risk for a relapse. Heat and cold can transiently increase symptoms.

Pregnancy can directly affect the susceptibility for relapse. Later pregnancy appears to offer a natural protection against relapses, and there are anecdotal reports of postpartum remission. However, pregnancy does not seem to influence long-term disability.

"The later course of ME. is difficult to predict, and may either become consistently severe, improve to a plateau, or be markedly relapse-remitting. In some, even prolonged severe incapacitation can be relieved by unpredictable remission, although relapse is always possible. The degree of impairment and complexity depends on the degree of diffuse brain injury and end organ involvement."[25]

Clinical subtypes[edit | edit source]

There are no standard subtypes. Some researchers and clinicians have proposed distinguishing between a relapsing-remitting and progressive course.[citation needed] However, it is difficult to distinguish between natural variation in the population of ME patients who might share a common disease process but owing to individual, genetic, or environmental differences, have different symptom clusters or disease course versus heterogeneity created by imprecise criteria and misdiagnosis.[26]

Kerr et al proposed 7 different subsets for “CFS” as it is defined today:[27]

  • Subtype 1 This is one of the more severe subtypes. Effects are cognitive, musculoskeletal, sleep-related and anxiety/depression.
  • Subtype 2 This is one of the more severe subtypes. Effects are musculoskeletal, pain and anxiety/depression.
  • Subtype 3 This subtype has the mildest symptoms.
  • Subtype 4 This subtype is dominated by cognitive issues.
  • Subtype 5 Effects are musculoskeletal and gastrointestinal.
  • Subtype 6 This subtype is dominated by post-exertional malaise (extreme crash after exercise or exertion.)
  • Subtype 7 This is one of the more severe subtypes. Effects are pain, infections, musculoskeletal, sleep-related, neurological, gastrointestinal, neurocognitive and anxiety/depression.

Pathophysiology[edit | edit source]

ME is a multi-system disease. Numerous biological abnormalities have been found in multiple bodily system, however no common, central cause or mechanism has yet been elucidated.

Central nervous system[edit | edit source]

Radiological research on ME has shown hypoperfusion of the brain stem and an abnormal response to exertion, but research on CFS is often inconsistent and must be interpreted with caution. For example, a reduced volume of grey matter may be a result of a lack of activity and is reversible with cognitive behavior therapy.

Autonomic nervous system[edit | edit source]

Peripheral nervous system[edit | edit source]

An inquest into the death of Sophia Mirza from ME found inflammation of the dorsal spine ganglia and liver abnormalities.

Musculoskeletal system[edit | edit source]

Immune system[edit | edit source]

According to a strictly immunological explanation of CFS, the inflammatory processes triggered by T cells create leaks in the blood-brain barrier (a capillary system that should prevent entrance of T-cells in the nervous system). These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins such as Rnase-L. Channelopathy, a reduced ability to move metabolites in and out of cells has been implicated in this process. This may also be applicable to ME.

Chronic infection[edit | edit source]

Some evidence shows viral infection of muscle and brain in at least a proportion of sufferers. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. A model for late ME has been proposed analogously to post-polio syndrome in which repaired nerve tissue forms inappropriately [The Late Effects of ME: Can they be distinguished from the Post-polio syndrome?].

Cardiovascular[edit | edit source]

Hemodynamic abnormalities are widely found, including serum and RBC hypovolemia, NMH, and cerebral hypoperfusion. Vascular and endothelial abnormalities have been published by MERUK. However, none of these studies used research criteria for ME so the results may not be applicable to ME.

Some cardiologic features such as cardiac insufficiency, inverted T-waves and myofiber disarray have been reported in CFS and recently added to by findings of reduced Q-value. This has led clinician and researcher Dr. Paul Cheney to posit that CFS is form of partially compensated cardiomyopathy in which orthostatic intolerance and rapid fatiguability are secondary protective mechanisms. Due to the heterogeneity of the population, a single cause is unlikely, but one-third of people with ME have abnormalities when tested with Holter monitors.

Gastrointestinal system[edit | edit source]

Sex differences[edit | edit source]

A CFS/ME Norwegian study shows the disease affects all ages, with two peak ages of 10-19 years and 30-39 years; it is more common in women than in men.[28] Research by the Open Medicine Foundation cited in its paper, Metabolic features of chronic fatigue syndrome which studied severe CFS, found that the disease is different in men and women but this is not related to testosterone or estrogen. Michael VanElzakker notes there are male and female differences in neuropathic pain. A study of UK and Dutch co-horts found "younger children had a more equal gender balance compared to adolescents and adults."[29]

Risk factors and potential causes[edit | edit source]

Risk factors[edit | edit source]

Potential causes[edit | edit source]

Although risk factors for myalgic encephalomyelitis have been identified, no single definitive virus has been found in all cases, which has led to the claim that ME is a common end path of a variety of infectious insults.[30][31][32][33] It is still possible ME involves some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations.[34][35] Several theories suggest that ME is an inappropriate immune response to an infection, a theory bolstered by the observation that there is sometimes a family history of autoimmune disease.[36] There is also a shift from the Th1 type of helper T cells, which fight infection, to the Th2 type, which are more active in allergy and more likely to attack the body.[37][38]

Viruses[edit | edit source]

Other theories describe ME as an immune response to a chronic infection. The association between ME and the Coxsackie B, HHV-6, and HHV-7 viruses[39][40] [41] suggests a potential viral contribution in at least some individuals. Evidence from epidemic myalgic encephalomyelitis strongly point to an enterovirus, however, in most outbreaks, no virus was successfully isolated.

Bacteria[edit | edit source]

Others believe ME may sometimes result from a chronic infection with spirochetal bacteria, such as Lyme disease. Another bacterium that has been implicated in ME is Chlamydia pneumoniae.[42] Protein findings relating to several infections have seen found in the oligoclonal bands ME patients.[43]

The Vagus nerve infection hypothesis accounts for why so many different infectious onsets could be responsible. The Vagus nerve runs from the brain stem and throughout the body and has an impact on many body systems.

Given the uncertainty regarding the cause, ME and CFS patients are barred from donating blood or organs in the United Kingdom, United States and New Zealand while symptoms persist.[44][45][46][47]

Treatments[edit | edit source]

There is no known cure for ME. Treatments for sleep problems, headaches and pain are utilized by some doctors for some patients although these are treating symptoms and not ME itself. Success of treating symptoms of ME is not well researched or documented.

Ampligen (Approved for ME/CFS in Argentina) and Rituximab are being trialled.

ME does not have a cure, though treatments including the antiviral Ampligen (now approved for use on ME/CFS patients in Argentina) and immune system modulator Rituximab are being trialled.[48]

Epidemiology[edit | edit source]

ME has been found world-wide, in at least 75 epidemics documented in published papers from the 1930s to the 1980s.[49] Epidemics often occur in enclosed communities such as schools and hospitals.

As observed in many autoimmune disorders, ME is more common in females than males; the mean sex ratio is approxmately 2-3 females for every male.[50] In children the sex ratio is approximately equal.[51]

Co-morbidities[edit | edit source]

Clinicians have observed several predisposing conditions, co-morbidities, overlapping conditions, and increased risks for secondary diseases in patients with ME. However, as no large-scale epidemiological studies, genetic studies, or family studies have been done, there is little than can be said definitively about the rate or underlying biological reasons for potentially related conditions. Different case definitions and resulting misdiagnoses add to the confusion. Moreover, certain conditions such as postural orthostatic tachycardia syndrome (POTS) and idiopathic intracranial hypertension (IIH) are symptoms that can occur in numerous conditions, including ME. The following are some syndromes and diseases that have been associated with (or in some cases, misdiagnosed as) ME:

See also[edit | edit source]

References[edit | edit source]

  1. Myalgic Encephalomyelitis - NORD
  2. Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) Medical Abnormalities Research Citations Compiled by Lisa Petrison, Ph.D.Updated April 4, 2016 - PDF
  3. History of chronic fatigue syndrome - International Classifications
  4. The Terminology of ME & CFS By Professor Malcolm Hooper - PDF
  5. 5.0 5.1 ME/CFS - Pathways to Prevention - NIH
  6. 6.0 6.1 Research Descriptions of M.E. - ME Action UK
  7. 7.0 7.1 The Clinical Features of Myalgic Encephalomyelitis Melvin Ramsay, M.D., 1986
  8. 8.0 8.1 What Is Post-exertional Malaise - Very Well - Adrienne Dellwo
  9. 9.0 9.1 Post Exertional Malaise - Very Well - Adrienne Dellwo
  10. 10.0 10.1 Chronic Fatigue Syndrome - Web MD
  11. 11.0 11.1 PEM Series - Solve ME/CFS - Jenny Spotila
  12. Postexertion 'Crash,' not Fatigue per se, Marks Syndrome - MedScape
  13. Progressive Myalgic Encephalomyelitis (ME) or A New Disease? A Case Report
  14. An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955 - The Medical Staff Of The Royal Free Hospital
  15. The Terminology of ME & CFS By Professor Malcolm Hooper
  16. MEAction RFI Poll Report (Part 1 of 3)
  17. ME Definition - Nightingale - PDF pg. 6
  18. ME Definition - Nightingale - PDF pg. 6
  19. Myalgic Encephalomyelitis - NORD
  20. What is ME - Invest in ME Research
  21. Myalgic Encephalomyelitis - NORD
  22. ME/CFS - Pathways to Prevention - Advancing the Research on Myalgic encephalomyelitis/Chronic Fatigue Syndrome
  23. US NIH Report Calls for UK Definition of ME/CFS to be Scrapped
  24. Dartmouth Hitchock - Myalgic Encephalomyelitis National Organization for Rare Disorders, Inc.
  25. What Is ME? - Disease course and clinical subtypes - A rainbow at night
  26. What Is ME? - Disease course and clinical subtypes - A rainbow at night
  27. Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes - JCP Online
  28. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine
  29. Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed
  30. Onset Patterns of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: A Mixed Method Approach - Meredyth Evans - DePaul University
  31. Vagus nerve infection hypothesis - MEpedia
  32. Chronic Fatigue Syndrome - Cleveland Clinic
  33. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. - PubMed
  34. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. RA Underhill - PubMed
  35. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome
  36. Klimas ME/CFS Genes Study - Face Book - Video
  37. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis - ScienceDirect
  38. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and the Potential Role of T Cells - Biological Markers and Guided Therapy, Vol. 1, 2014, no. 1, 25 -38 - PDF
  39. Coxsackie B viruses and myalgic encephalomyelitis.
  40. Ramsay Research Team 5 – The Potential Role of HHV-6 in ME/CFS
  41. Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
  42. Chlamydia Pneumoniae - Stanford Myalgic Encephalomyelitis/Chronic Fatigue syndrome Initiative
  43. CSF Oligoclonal Banding - NY Times
  44. People with ME/CFS to be permanently excluded from giving blood in the UK from 1 November this year – Department of Health announcement - ME Association
  45. American Red Cross Statement on XMRV and Chronic Fatigue Syndrome - American Red Cross
  46. Chronic fatigue patients barred from blood donation - Washington Post - By: Rob Stein - Dec 3, 2010
  47. - NZBlood
  48. Chronic Fatigue Syndrome & Myalgic Encephalomyelitis Experimental Treatments - ProHealth (Ampligen and Rituximab Tabs
  49. Myalgic Encephalomyelitis: The medical facts - What causes Myalgic Encephalomyelitis? Are there outbreaks of M.E.?
  50. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012 - BMC Medicine
  51. Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open - PubMed