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List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis

2023-12-21T06:57:01Z

JenB:Cd4 cd8 ratio

[[Myalgic encephalomyelitis]]/[[chronic fatigue syndrome]] is a complex multi-system disease and biological abnormalities in patients have been found affecting multiple bodily systems. No single [[diagnostic biomarker|biomarker]]-based diagnostic test has been validated but patients have a range abnormal physical findings affecting multiple bodily systems.<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012
| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf }}</ref> The CDC states that diagnosing ME/CFS relies on a physical and psychiatric assessment, observations, medical history, clinical interview, and results from a mix of blood and urine tests.<ref name="CDC2020diagnosis">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html | title = Diagnosis of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last = Centers of Disease Control|first = | authorlink = Centers for Disease Control and Prevention | date = 2019-05-15 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|url-status=|access-date=2020-09-26}}</ref>

== Nervous system ==
===Brain ===
{{Main article|Brain}}
*Progressive brain changes<ref name="Shan2016"/>

=== Central nervous system ===
{{Main article |page_name =Central nervous system}}
* increased [[Ventricular system|ventricular]] [[lactate]]<ref name="Mathew2009">{{Cite journal | last = Mathew|first = Sanjay J. | last2 = Mao | first2 = Xiangling | last3 = Keegan | first3 = Kathryn A. | last4 = Levine | first4 = Susan M. | authorlink4 = Susan Levine | last5 = Smith | first5 = Eric L.P. | last6 = Heier | first6 = Linda A. | last7 = Otcheretko | first7 = Viktor | last8 = Coplan | first8 = Jeremy D. | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = Apr 2009 | title = Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: anin vivo3.0 T1H MRS imaging study|url=https://onlinelibrary.wiley.com/doi/full/10.1002/nbm.1315|journal=NMR in Biomedicine|language=en|volume=22|issue=3|pages=251–258|doi=10.1002/nbm.1315|issn=0952-3480}}</ref><ref name="Murrough2010">{{Cite journal | last = Murrough|first = James W. | last2 = Mao | first2 = Xiangling | last3 = Collins | first3 = Katherine A. | last4 = Kelly | first4 = Chris | last5 = Andrade | first5 = Gizely | last6 = Nestadt | first6 = Paul | last7 = Levine | first7 = Susan M. | authorlink7 = Susan Levine | last8 = Mathew | first8 = Sanjay J. | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = Jul 2010 | title = Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder | url =https://www.ncbi.nlm.nih.gov/pubmed/20661876|journal=NMR in Biomedicine|volume=23|issue=6 | pages = 643–650|doi=10.1002/nbm.1512|issn=1099-1492|pmid=20661876}}</ref><ref name="Shungu2012">{{Cite journal | last = Shungu | first = Dikoma C. | authorlink1 = Dikoma Shungu | last2 = Weiduschat | first2 = Nora | last3 = Murrough | first3 = James W. | last4 = Mao | first4 = Xiangling | last5 = Pillemer | first5 = Sarah | last6 = Dyke | first6 = Jonathan P. | last7 = Medow | first7 = Marvin S. | last8 = Natelson | first8 = Benjamin H. | authorlink8 = Benjamin Natelson | last9 = Stewart | first9 = Julian M. | date = Sep 2012 | title = Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology|url=https://www.ncbi.nlm.nih.gov/pubmed/22281935|journal=NMR in biomedicine|volume=25|issue=9|pages=1073–1087|doi=10.1002/nbm.2772|issn=1099-1492|pmc=3896084|pmid=22281935}}</ref><ref name="Natelson2017">{{Cite journal | last = Natelson | first = Benjamin H. | authorlink1 = Benjamin Natelson | last2 = Vu | first2 = Diana | last3 = Coplan | first3 = Jeremy D. | last4 = Mao | first4 = Xiangling | last5 = Blate | first5 = Michelle | last6 = Kang | first6 = Guoxin | last7 = Soto | first7 = Eli | last8 = Kapusuz | first8 = Tolga | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = 2017-01-02 | title = Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1280114?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=1|pages=15–20|doi=10.1080/21641846.2017.1280114|issn=2164-1846|pmc=5754037|pmid=29308330}}</ref>
* neuroinflammation<ref name="Nakatomi2014">{{Cite journal | last = Nakatomi|first = Yasuhito | last2 = Mizuno | first2 = Kei | last3 = Ishii | first3 = Akira | last4 = Wada | first4 = Yasuhiro | last5 = Tanaka | first5 = Masaaki | last6 = Tazawa | first6 = Shusaku | last7 = Onoe | first7 = Kayo | last8 = Fukuda | first8 = Sanae | last9 = Kawabe | first9 = Joji | date = 2014-06-01 | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study|url=http://jnm.snmjournals.org/content/55/6/945|journal=Journal of Nuclear Medicine|language=en|volume=55|issue=6 | pages = 945–950|doi=10.2967/jnumed.113.131045|issn=0161-5505|pmid=24665088}}</ref><ref name="Zeineh2014">{{citation | last1 = Zeineh | first1 = Michael M | authorlink1 = Michael Zeineh | last2 = Kang | first2 = James | authorlink2 = James Kang | last3 = Atlas | first3 = Scott W | authorlink3 = Scott Atlas | last4 = Raman | first4 = Mira M | authorlink4 = Mira Raman | last5 = Reiss | first5 = Allan L | authorlink5 = Allan Reiss | last6 =Norris | first6 = Jane L | authorlink6 = Jane Norris | last7 =Valencia | first7 = Ian | authorlink7 = Ian Valencia | last8 =Montoya | first8 = Jose G | authorlink8 = Jose Montoya | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome| journal = Radiology | volume = 274 | issue = 2| pages = 517–526 | date = 2014-10-29| doi = 10.1148/radiol.14141079| url = http://pubs.rsna.org/doi/abs/10.1148/radiol.14141079}}</ref><ref name="Mueller2019">{{Cite journal|url=https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink=Christina Mueller | last2 = Lin | first2 = Joanne C | authorlink2 = Joanne Lin | date = 2019 | doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|url-status=|access-date=2019-01-17 | authorlink3 = Sulaiman Sheriff | authorlink4 = Andrew Maudsley | authorlink5 = Jarred Younger | last3 = Sheriff | last4 = Maudsley | last5 = Younger | first3 = Sulaiman | first4 = Andrew A | first5 = Jarred W|volume=|issue=|pages= | page = |journal=Brain Imaging and Behavior}}</ref><ref name="RamsayAward20190117">{{Cite web|url=http://go.solvecfs.org/webmail/192652/97033877/74d435097e87231f24cffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1 | title = Brain Imaging and Behavior publication from Dr. Jarred Younger’s SMCI Ramsay pilot study supports involvement of neuroinflammation in ME/CFS|website=go.solvecfs.org|access-date=2019-01-17 | date = | last = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
* reduced [[Grey matter|grey]]<ref name="Puri2012">{{Cite journal | last = Puri|first = B K | last2 = Jakeman | first2 = P M | last3 = Agour | first3 = M | last4 = Gunatilake | first4 = K D R | last5 = Fernando | first5 = K A C | last6 = Gurusinghe | first6 = A I | last7 = Treasaden | first7 = I H | last8 = Waldman | first8 = A D | last9 = Gishen | first9 = P | date = Jul 2012 | title = Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study|url=https://www.birpublications.org/doi/full/10.1259/bjr/93889091|journal=The British Journal of Radiology|language=en|volume=85|issue=1015| pages = e270–e273|doi=10.1259/bjr/93889091|issn=0007-1285|pmc=3474083|pmid=22128128}}</ref> and [[white matter]]<ref name="Shan2016">{{Cite journal | last = Shan | first = Zack Y. | authorlink = Zack Shan | last2 = Kwiatek | first2 = Richard | last3 = Burnet | first3 = Richard | last4 = Del Fante | first4 = Peter | last5 = Staines | first5 = Donald R. | last6 = Marshall-Gradisnik | first6 = Sonya M. | last7 = Barnden | first7 = Leighton R. | date = 2016-04-28 | title = Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study|url=https://onlinelibrary.wiley.com/doi/full/10.1002/jmri.25283|journal=Journal of Magnetic Resonance Imaging|language=en|volume=44|issue=5|pages=1301–1311|doi=10.1002/jmri.25283|issn=1053-1807|pmc=5111735|pmid=27123773}}</ref><ref name="Puri2012" />
* [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|widespread metabolite abnormalities]]<ref name="Mueller2019"/>

=== Autonomic nervous system ===
{{Main article |page_name =Autonomic nervous system}}
* Orthostatic intolerance<ref>Gerwin Morris, Michael Maes, see citations 12 through 27 in [http://www.biomedcentral.com/1741-7015/11/205 "Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics"] BMC Medicine, 17 September 2013</ref><ref>{{Cite journal | last = Miwa | first = K | date = Jul 2015 | title = Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle|url=https://www.ncbi.nlm.nih.gov/pubmed/24736946|journal=Heart and Vessels|volume=30|issue=4 | pages = 484–489|via=}}</ref>

=== Peripheral nervous system ===
{{Main article |page_name =Peripheral nervous system}}

== Muscular system ==
{{Main article |page_name =Muscle}}
*[[Mitochondrion|mitochondria]]l abnormalities found via [[muscle biopsy]] including: mitochondrial degeneration,<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref> deletions of mitochondrial DNA,<ref name=":0">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref><ref>{{Cite journal | last = Zhang|first = C. | last2 = Baumer | first2 = A. | last3 = Mackay | first3 = I.R. | last4 = Linnane | first4 = A.W. | last5 = Nagley | first5 = P. | date = Apr 1995 | title = Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/7633428|journal=Human Molecular Genetics|volume=4|issue=4 | pages = 751–754|issn=0964-6906|pmid=7633428}}</ref> the reduction of mitochondrial activity<ref name=":0" />
*Increased urinary [[creatine]] excretion during relapses<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>
*Increased [[creatine kinase]] ([[postviral fatigue syndrome]])
*Persistence of [[enterovirus]]es in muscle tissue<ref name=":1">{{Cite journal | last = Gow|first = J.W. | last2 = Behan | first2 = W. M.H. | last3 = Simpson | first3 = K. | last4 = McGarry | first4 = F. | last5 = Keir | first5 = S. | last6 = Behan | first6 = P.O. | date = 1994-01-01 | title = Studies on Enterovirus in Patients with Chronic Fatigue Syndrome|url=https://academic.oup.com/cid/article-abstract/18/Supplement_1/S126/316946|journal=Clinical Infectious Diseases|language=en|volume=18|issue=Suppl 1|pages=S126–S129|doi=10.1093/clinids/18.Supplement_1.S126|issn=1537-6591}}</ref><ref name=":2">{{Cite journal | last = Cunningham|first = Louise | last2 = Bowles | first2 = N.E. | last3 = Lane | first3 = R. J.M. | last4 = Dubowitz | first4 = V. | last5 = Archard | first5 = L.C. | date = 1990 | title = Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-71-6-1399|journal=Journal of General Virology|volume=71|issue=6|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399}}</ref><ref name=":3">{{Cite journal | last = Archard | first = LC | last2 = Bowles | first2 = NE | last3 = Behan | first3 = PO | last4 = Bell | first4 = EJ | last5 = Doyle | first5 = D | date = 1988-06-01 | title = Postviral Fatigue Syndrome: Persistence of Enterovirus RNA in Muscle and Elevated Creatine Kinase, Postviral Fatigue Syndrome: Persistence of Enterovirus RNA in Muscle and Elevated Creatine Kinase|url=https://doi.org/10.1177/014107688808100608|journal=Journal of the Royal Society of Medicine|language=en|volume=81|issue=6 | pages = 326–329|doi=10.1177/014107688808100608|issn=0141-0768|pmc=1291623|pmid=3404526}}</ref><ref name=":4">{{Cite journal | last = Gow|first = J.W. | last2 = Behan | first2 = W.M. | last3 = Clements | first3 = G.B. | last4 = Woodall | first4 = C. | last5 = Riding | first5 = M. | last6 = Behan | first6 = P.O. | date = 1991-03-23 | title = Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome.|url=https://www.bmj.com/content/302/6778/692|journal=BMJ|language=en|volume=302|issue=6778 | pages = 692–696|doi=10.1136/bmj.302.6778.692|issn=0959-8138|pmid=1850635}}</ref>
*abnormalities of [[AMPK]] activation and glucose uptake in cultured skeletal muscle cells<ref name="BrownAE2015">{{Citation | last1 = Brown | first1 = Audrey E | authorlink1 = Audrey Brown | last2 = Jones | first2 = David E | authorlink2 = David Jones | last3 = Walker | first3 = Mark | authorlink3 = Mark Walker | last4 = Newton | first4 = Julia L | authorlink4 = Julia Newton | title = Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells | journal = PLoS One | volume = 10 | issue = 4 | date = 2 Apr 2015 | pmid = 25836975 | doi = 10.1371/journal.pone.0122982 | url = http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982 }}</ref><ref name="Wellness20150420">{{citation | last1 = Dobberstein | first1 = Linda J. | authorlink1 = | title = Master Enzyme Switch Deactivated In Chronic Fatigue Syndrome and Fibromyalgia | journal = Wellness Resources | date = 20 Apr 2015 | url = http://www.wellnessresources.com/health/articles/master_enzyme_switch_deactivated_in_chronic_fatigue_syndrome_and_fibromyalg/ }}</ref>

== Immune system ==
{{Main article |page_name =Immune system}}
=== Immune dysregulation ===
* [[Natural killer cell]] function is reduced<ref>{{Cite journal | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis|url=http://www.ncbi.nlm.nih.gov/pubmed/24343819|journal=International Immunology | date = Apr 2014|issn=1460-2377|pmid=24343819|pages=233–242|volume=26|issue=4|doi=10.1093/intimm/dxt068|first = Ekua Weba | last = Brenu | first2 = Teilah K. | last2 = Huth | first3 = Sharni L. | last3 = Hardcastle | first4 = Kirsty | last4 = Fuller | first5 = Manprit | last5 = Kaur | first6 = Samantha | last6 = Johnston | first7 = Sandra B. | last7 = Ramos | first8 = Don R. | last8 = Staines | first9 = Sonya M. | last9 = Marshall-Gradisnik}}</ref><ref>{{Cite journal | last = Victoria Scott | first = David Strayer | date = 2015 | title=Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity|url=https://www.omicsonline.org/open-access/low-nk-cell-activity-in-chronic-fatigue-syndrome-cfs-and-relationship-to-symptom-severity-2155-9899-1000348.php?aid=59415|journal=Journal of Clinical & Cellular Immunology|language=en|volume=6|issue=4|doi=10.4172/2155-9899.1000348|issn=2155-9899}}</ref>
* [[Cytokine]] dysregulation<ref name="Montoya, 2017">{{citation | last1 = Montoya | first1 = Jose G. | authorlink1 = Jose Montoya | last2 = Holmes | first2 = Tyson H. | authorlink2 = | last3 = Anderson | first3 = Jill N. | authorlink3 = | last4 = Maecker | first4 = Holden T. | authorlink4 = | last5 = Rosenberg-Hasson | first5 = Yael | authorlink5 = | last6 = Valencia | first6 = Ian J. | authorlink6 = | last7 = Chu | first7 = Lily | authorlink7 = Lily Chu | last8 =Younger | first8 = Jarred W. | authorlink8 = Jarred Younger | last9 =Tato | first9 = Cristina M. | authorlink9 = | last10 = Davis | first10 = Mark M. | authorlink10 = Mark Davis | title = Cytokine signature associated with disease severity in chronic fatigue syndrome patients | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 34 | pages = E7150-E7158 | date = 2017 | pmid = | doi = 10.1073/pnas.1710519114 }}</ref><ref>[http://www.meaction.net/2015/12/07/study-finds-evidence-of-downregulated-immune-system-in-mecfs-patients Study finds evidence of downregulated immune system in ME/CFS patients - MEAction - Landi, et al.]</ref><ref>[http://microbediscovery.org/2017/04/04/new-research-discovers-evidence-of-atypical-classical-mecfs/ New Research Discovers Evidence of Atypical & Classical ME/CFS - The Microbe Discovery Project - Apr 4, 2017]</ref>
* Elevated [[regulatory T cell]]s<ref>{{Cite journal | last = Brenu|first = Ekua Weba | last2 = Huth | first2 = Teilah K. | last3 = Hardcastle | first3 = Sharni L. | last4 = Fuller | first4 = Kirsty | last5 = Kaur | first5 = Manprit | last6 = Johnston | first6 = Samantha | last7 = Ramos | first7 = Sandra B. | last8 = Staines | first8 = Don R. | last9 = Marshall-Gradisnik | first9 = Sonya M. | date = Apr 2014 | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis|url=http://www.ncbi.nlm.nih.gov/pubmed/24343819|journal=International Immunology|volume=26|issue=4|pages=233–242|doi=10.1093/intimm/dxt068|issn=1460-2377|pmid=24343819}}</ref>
* increased [[mast cell]] populations<ref>{{Cite journal | last = Rönnberg|first = E | last2 = Calounova | first2 = G | last3 = Pejler | first3 = G | date = June 2017 | title = Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients|url=https://www.ncbi.nlm.nih.gov/pubmed/27362406|journal=Asian Pac J Allergy Immunol|volume=35|issue=2 | pages = 75-81|via=}}</ref>
* elevated anti-cholinergic [[Muscarinic acetylcholine receptor|muscarinic]], Β-adrenergic,<ref>{{Cite journal | last = Loebel|first = Madlen | last2 = Grabowski | first2 = Patricia | last3 = Heidecke | first3 = Harald | last4 = Bauer | first4 = Sandra | last5 = Hanitsch | first5 = Leif G. | last6 = Wittke | first6 = Kirsten | last7 = Meisel | first7 = Christian | last8 = Reinke | first8 = Petra | last9 = Volk | first9 = Hans-Dieter | date = Feb 2016 | title = Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26399744|journal=Brain, Behavior, and Immunity|volume=52 | pages = 32–39|doi=10.1016/j.bbi.2015.09.013|issn=1090-2139|pmid=26399744}}</ref> [[phosphatidylinositol]]<ref>{{Cite journal | last = Maes | first = Michael | last2 = Mihaylova | first2 = Ivanka | last3 = Leunis | first3 = Jean-Claude | date = Dec 2007 | title = Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression | url =https://www.ncbi.nlm.nih.gov/pubmed/18063934|journal=Neuro Endocrinology Letters|volume=28|issue=6 | pages = 861–867|issn=0172-780X|pmid=18063934}}</ref> and [[serotonin]]<ref>{{Cite journal | last = Maes | first = Michael | last2 = Ringel | first2 = Karl | last3 = Kubera | first3 = Marta | last4 = Anderson | first4 = George | last5 = Morris | first5 = Gerwyn | last6 = Galecki | first6 = Piotr | last7 = Geffard | first7 = Michel | date = 2013-09-05 | title = In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation | url =https://www.ncbi.nlm.nih.gov/pubmed/23664637|journal=Journal of Affective Disorders|volume=150|issue=2|pages=223–230|doi=10.1016/j.jad.2013.03.029|issn=1573-2517|pmid=23664637}}</ref> autoantibodies
* Reduced CD4+ function<ref name=":5">{{Cite journal|title=Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations|date=2020-03-02|url=https://pubmed.ncbi.nlm.nih.gov/31830003/|journal=The Journal of Clinical Investigation|volume=130|issue=3|pages=1491–1505|last=Mandarano|first=Alexandra H.|last2=Maya|first2=Jessica|last3=Giloteaux|first3=Ludovic|last4=Peterson|first4=Daniel L.|last5=Maynard|first5=Marco|last6=Gottschalk|first6=C. Gunnar|last7=Hanson|first7=Maureen R.|doi=10.1172/JCI132185|pmc=7269566|pmid=31830003|issn=1558-8238}}</ref> and reduced CD4+ count<ref name=":6">{{Cite journal|title=Study of immune alterations in patients with chronic fatigue syndrome with different etiologies|date=2004|url=https://pubmed.ncbi.nlm.nih.gov/15345193/|journal=International Journal of Immunopathology and Pharmacology|volume=17|issue=2 Suppl|pages=57–62|last=Racciatti|first=D.|last2=Dalessandro|first2=M.|last3=Delle Donne|first3=L.|last4=Falasca|first4=K.|last5=Zingariello|first5=P.|last6=Paganelli|first6=R.|last7=Pizzigallo|first7=E.|last8=Vecchiet|first8=J.|doi=10.1177/03946320040170S210|pmid=15345193|issn=0394-6320}}</ref>
* Reduced CD8+ function<ref name=":5" /> and reduced CD8+ count<ref name=":6" />
* Lowered CD4+/CD8+ ratio<ref>{{Cite journal|title=Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers|date=2015-01-01|url=https://europepmc.org/article/med/26707044|journal=Neuro endocrinology letters|volume=36|issue=5|pages=439–446|last=Maes|first=Michael|last2=Bosmans|first2=Eugene|last3=Kubera|first3=Marta|pmid=26707044|issn=2354-4716}}</ref>

=== Chronic infection ===
* [[Enterovirus]]: Persistence of [[enterovirus]]es in muscle tissue;<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> brain;<ref name="McGarry19942">{{citation | last1 = McGarry | first1 = Frances | author-link1 = Frances McGarry | last2 = Gow | first2 = John | authorlink2 = John Gow | last3 = Behan | first3 = Peter O | authorlink3 = Peter O Behan | title = Enterovirus in the Chronic Fatigue Syndrome | journal = Annals of Internal Medicine | volume = 120 | issue = 11| pages = 972–973 | date = Jun 1, 1994 | doi = 10.7326/0003-4819-120-11-199406010-00020 | url = http://www.ncbi.nlm.nih.gov/pubmed/8172448 }}</ref> and gut;<ref name="ChiaJKS2016">{{Cite journal | last1 = Chia | first1 = JKS | authorlink1 = John Chia | last2 = Chia | first2 = AY | authorlink2 = Andrew Chia | title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach | journal = Journal of Clinical Pathology | volume = 61 | issue = 1| pages = 43–48 | date = Jan 1, 2008 | pmid = 17872383 | doi = 10.1136/jcp.2007.050054 | url = http://jcp.bmj.com/content/61/1/43 }}</ref> increased detection of viral [[RNA]] via PCR; increased [[:Category:Antibodies|antibodies]]
* [[Herpesvirus]]{{citation needed}}

== Lymphatic system ==

== Cardiovascular system ==

{{Main article|page_name =Cardiovascular system}}{{Main article|page_name =Cardiac problems in ME/CFS}}

=== Heart ===
* Smaller than normal [[left ventricle]] of the [[heart]],<ref name=":8">Miwa K., [http://www.ncbi.nlm.nih.gov/pubmed/24736946 "Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle"] Heart Vessels, July 2015</ref><ref>Hollingsworth K.G [http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1365-2796.2011.02429.x/ "Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging"] J Intern Med 2012; 271: 264–270.</ref><ref name="Olimulder, 2016">{{Cite journal | last1 = Olimulder | first1 = M.A.G.M. | authorlink1 = | last2 = Galjee | first2 = M.A. | authorlink2 = | last3 = Wagenaar | first3 = L.J. | authorlink3 = | last4 = van Es | first4 = J. | authorlink4 = | last5 = van der Palen | first5 = J. | authorlink5 = | last6 = Visser | first6 = F.C. | authorlink6 = | last7 =Vermeulen | first7 = R.C.W. | authorlink7 = | last8 = von Birgelen | first8 = C. | authorlink8 = | title = Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging | journal = Netherlands Heart Journal | volume = 24 | pages = 709–716 | date = 2016 | url = https://link.springer.com/article/10.1007/s12471-016-0885-8 | doi = 10.1007/s12471-016-0885-8 }}</ref><ref>[http://openheart.bmj.com/content/3/1/e000381.long Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study]</ref> [[small heart syndrome]],<ref name=":8" /> and low [[Cardiovascular system|cardiac]] output.<ref>Miwa K., Fujita M., [http://www.ncbi.nlm.nih.gov/pubmed/19881233 "Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome"] Intern Med, 2009;48(21):1849-54</ref>
* Mean age of death from heart failure of [[chronic fatigue syndrome|CFS]] patients is 58.7 years as compared to 83.1 years for the general population.<ref>Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S, [http://www.ncbi.nlm.nih.gov/pubmed/16844674 "Causes of death among patients with chronic fatigue syndrome"] Health Care Women Int., 27(7): 615-626. 2006</ref>
=== Circulation ===
* reduced blood flow to the [[Brain|brain,]]<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 = Benjamin | authorlink1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | last3 = Stegner | first3 = Aaron J | last4 = Lange | first4 = Gudrun | authorlink4 = Gudrun Lange | last5 = Vu | first5 = Diana | last6 = Blate | first6 = Michelle | last7 = Kang | first7 = Guoxin | last8 = Soto | first8 = Eli | last9 = Kapusuz | first9 = Tolga | last10 = Shungu | first10 = Dikoma C | authorlink10 = Dikoma Shungu | title=Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | date = 2017 | journal=Journal of the Neurological Sciences|volume=375|issue= | page = 411-416|doi=10.1016/j.jns.2017.02.046|pmid=|quote=}}</ref><ref name=":32">{{Cite journal | last = Costa|first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8542261|journal=QJM: monthly journal of the Association of Physicians|volume=88|issue=11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name=":10">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Del Fante | first8 = Peter | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692|journal=NMR in Biomedicine|language=en|volume=24|issue=10|pages=1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc = 4369126|pmid=21560176}}</ref><ref>{{Cite journal | last = Biswal|first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | authorlink1 = Benjamin Natelson | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666|journal=Journal of the Neurological Sciences|volume=301|issue=1 | pages = 9–11 |doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name=":11">{{Cite journal | last = Yoshiuchi|first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | authorlink3 = Benjamin Natelson | date = 2006 | title=Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x|journal=Clinical Physiology and Functional Imaging|language=en|volume=26|issue=2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.|url=http://europepmc.org/abstract/med/1491843|journal=Nuclear medicine communications|volume=13|issue=10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao|first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://cvi.asm.org/content/1/2/222|journal=Clinical and Diagnostic Laboratory Immunology|language=en|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome|url=http://www.sciencedirect.com/science/article/pii/S0002934398001752|journal=The American Journal of Medicine|volume=105|issue=3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref> even in the absence of [[Postural orthostatic tachycardia syndrome|POTS]]/[[Neurally mediated hypotension|NMH]]<ref>{{Citation | title = CMRC Conference 2017 day 1- Prof Dr Frans Visser |url =https://www.youtube.com/watch?v=IWRA23D_MUg|language=en|access-date=2019-09-03}}</ref>
* reduced blood flow to the heart<ref>{{Cite journal | last = Patrick Neary|first = J. | last2 = Roberts | first2 = Andy D.W. | last3 = Leavins | first3 = Nina | last4 = Harrison | first4 = Michael F. | last5 = Croll | first5 = James C. | last6 = Sexsmith | first6 = James R. | date = Nov 2008 | title = Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1475-097X.2008.00822.x|journal=Clinical Physiology and Functional Imaging|volume=28|issue=6 | pages = 364–372|doi=10.1111/j.1475-097x.2008.00822.x|issn=1475-0961}}</ref><ref>{{Cite journal | last = Peterson | first = PK | last2 = Sirr | first2 = SA | last3 = Grammith | first3 = FC | last4 = Schenck | first4 = CH | last5 = Pheley | first5 = AM | last6 = Hu | first6 = S | last7 = Chao | first7 = C C | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC368231/|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
*peripheral endothelial dysfunction, which is an established risk factor for cardiovascular disease<ref name="endothelial2020">{{Cite journal | last = Scherbakov|first = Nadja | authorlink = | last2 = Szklarski | first2 = Marvin | author-link2 = | last3 = Hartwig | first3 = Jelka | author-link3 = | last4 = Sotzny | first4 = Franziska | author-link4 = Franziska Sotzny | last5 = Lorenz | first5 = Sebastian | author-link5 = | last6 = Meyer | first6 = Antje | authorlink6 = Antje Meyer | last7 = Grabowski | first7 = Patricia | last8 = Doehner | first8 = Wolfram | last9 = Scheibenbogen | first9 = Carmen | authorlink9 = Carmen Scheibenbogen | date = 2020 | title=Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ehf2.12633|journal=ESC Heart Failure|language=en|volume=7|issue=3|pages=1064–1071|doi=10.1002/ehf2.12633|issn=2055-5822|pmc = 7261521|pmid=32154656|access-date=|quote=|via=}}</ref>

=== Blood vessels ===

=== Blood ===
{{Main article|Brain}}
* reduced [[blood]] volume<ref>{{Cite journal | last = Hurwitz|first = BE | last2 = Coryell | first2 = VT | last3 = Parker | first3 = M | last4 = Martin | first4 = P | last5 = LaPerriere .... | first5 = A | last6 = Bilsker | first6 = MS | date = | title = Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function | url =http://www.clinsci.org/content/118/2/125|journal=Clinical Science|volume=118|issue=2|pages=125-135|via=}}</ref><ref>{{Cite journal | last = Streeten | first = DHP | last2 = Bell | first2 = D | date = 1998 | title=Circulating Blood Volume in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n01_02|journal=Journal of Chronic Fatigue Syndrome|volume=4 | pages = 3-11|via=}}</ref>
* abnormally shaped of [[Red blood cell|red blood cells]]<ref name="Simpson1989">{{Citation | last1 = Simpson | first1 = LO | authorlink1 = Leslie Simpson | title = Nondiscocytic erythrocytes in myalgic encephalomyelitis | journal = The New Zealand Medical Journal | volume = 102 | issue = 864 | pages = 126-127 | date = 1989 | pmid = 2927808 | doi = }}</ref><ref>{{Cite journal | last = Richards | first = RS | last2 = Wang | first2 = L | last3 = Jelinek | first3 = H | date = Jan 2007 | title = Erythrocyte oxidative damage in chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/pii/S0188440906002992|journal=Archives of Medical Research|volume=38|issue=1 | pages = 94-98|via=}}</ref>
* reduced oxygen uptake in [[hemoglobin]]<ref>{{Cite journal | last = Miller | first = Ruth R | last2 = Reid | first2 = W Darlene | last3 = Mattman | first3 = Andre | last4 = Yamabayashi | first4 = Cristiane | last5 = Steiner | first5 = Theodore | last6 = Parker | first6 = Shoshana | last7 = Gardy | first7 = Jennifer | last8 = Tang | first8 = Patrick | last9 = Patrick | first9 = David M | date = 2015-05-20 | title = Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case–control study|url=http://doi.org/10.1186/s12967-015-0527-8|journal=Journal of Translational Medicine|language=en|volume=13|issue=1|doi=10.1186/s12967-015-0527-8|issn=1479-5876|pmc=4438583|pmid=25990639}}</ref>

== Digestive system ==

=== Gastrointestinal tract ===
{{Main article |page_name = Gastrointestinal tract}}
* lower levels of [[Bifidobacteria]], [[Escherichia coli]] and higher levels of [[aerobic bacteria]],<ref>{{Cite journal | title = Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value|url=http://www.medical-hypotheses.com/article/S0306-9877(03)00096-3/abstract|journal=Medical Hypotheses | date = Jun 2003|issn=0306-9877 | pages = 915–923|volume=60|issue=6|doi=10.1016/S0306-9877(03)00096-3|language=English|first = Alan C | last = Logan | first2 = A | last2 = Venket Rao | first3 = Dinaz | last3 = Irani}}</ref> in particular [[Enterococcus]] and [[Streptococcus]] species<ref>{{Cite journal | title = Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome|url=http://www.ncbi.nlm.nih.gov/pubmed/19567398|journal=In Vivo (Athens, Greece) | date = Jul 2009|issn=0258-851X|pmid=19567398 | pages = 621–628|volume=23|issue=4|first = John R. | last = Sheedy | first2 = Richard E.H. | last2 = Wettenhall | first3 = Denis | last3 = Scanlon | first4 = Paul R. | last4 = Gooley | first5 = Donald P. | last5 = Lewis | first6 = Neil | last6 = McGregor | first7 = David I. | last7 = Stapleton | first8 = Henry L. | last8 = Butt | first9 = Kenny L. | last9 = DE Meirleir}}</ref>
* higher levels of enterococcus bacteria in CFS patients were associated with more severe neurological and cognitive dysfunction<ref>https://getinfo.de/en/search/id/BLCP%3ACN055885616/%60Bacterial-Colonosis-in-Patients-with-Persistent/</ref>
* Significantly increased proportions of Firmicutes<ref>{{Cite journal | title = High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients|url=https://www.sciencedirect.com/science/article/pii/S1075996413000929|journal=Anaerobe | date = 2013-08-01|issn=1075-9964 | pages = 50–56|volume=22|doi=10.1016/j.anaerobe.2013.06.002|language=en}}</ref><ref name=":7">{{Cite journal | last = Giloteaux | first = Ludovic | last2 = Goodrich | first2 = Julia K. | last3 = Walters | first3 = William A. | last4 = Levine | first4 = Susan M. | author-link4 = Susan Levine | last5 = Ley | first5 = Ruth E. | last6 = Hanson | first6 = Maureen R. | date = 2016-06-23 | title = Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918027/|journal=Microbiome|volume=4|doi=10.1186/s40168-016-0171-4|issn=2049-2618|pmc=4918027|pmid=27338587}}</ref> and Bacteroides<ref name=":7" />
* CFS patients may suffer from [[small intestinal bacterial overgrowth]] (SIBO) at high rates<ref name="Pimentel2000">{{Citation | last1 = Pimentel | first1 = M | authorlink1 = Mark Pimentel | last2 = Hallegua | first2 = D | authorlink2 = David Hallegua | last3 = Chow | first3 = EJ | authorlink3 = Evelyn Chow | last4 = Wallace | first4 = D | authorlink4 = Daniel Wallace | last5 = Bonorris | first5 = G | authorlink5 = George Bonorris | last6 = Lin | first6 = HC | authorlink6 = Henry Lin | title = Eradication of small intestinal bacterial overgrowth decreases symptoms in chronic fatigue syndrome: A double blind, randomized study | journal = Gastroenterology | volume = 118 | issue = 4| pages = 414 | date = 1 Apr 2000 | doi = 10.1016/S0016-5085(00)83765-8 | url = http://www.gastrojournal.org/article/S0016508500837658/abstract }}</ref>
* Higher levels of serum [[Immunoglobulin A|IgA]] and [[Immunoglobulin M|IgM]] against [[lipopolysaccharide]]s (LPS), a major component of the outer membrane of [[gram-negative bacteria]], indicating translocation.<ref>{{Cite journal | last = Maes | first = Michael | last2 = Mihaylova | first2 = Ivana | last3 = Leunis | first3 = Jean-Claude | date = 2007-04-01 | title = Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): Indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut–intestinal permeability|url=http://www.sciencedirect.com/science/article/pii/S0165032706003557|journal=Journal of Affective Disorders|language=en|volume=99|issue=1|pages=237–240|doi=10.1016/j.jad.2006.08.021|issn=0165-0327}}</ref> Serum [[Immunoglobulin A|IgA]] was significantly correlated to the severity of illness.

=== Liver ===
* Reduced [[liver]] volume<ref>{{Cite journal | title = Liver volume is lower and associates with resting and dynamic blood pressure variability in chronic fatigue syndrome|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1488525|journal=Fatigue: Biomedicine, Health & Behavior | date = 2018-06-18|issn=2164-1846|pages=141–152|volume=6|issue=3|doi=10.1080/21641846.2018.1488525|language=en | first = Pawel | last = Zalewski | first2 = Andreas | last2 = Finkelmeyer | first3 = James | last3 = Frith | first4 = Laura | last4 = Maclachlan | first5 = Andrew | last5 = Blamire | first6 = Julia L. | last6 = Newton}}</ref>

== Nutrition ==
* low red blood cell [[magnesium]]<ref name="cfs_and_blood_mg">{{Citation | last1 = I.M. | first1 = Cox | authorlink1 = | last2 = M.J. | first2 = Campbell | authorlink2 = | last3 = D. |first3 = Dowson | authorlink3 = | title = Red blood cell magnesium and chronic fatigue syndrome | journal = The Lancet
| year = 1991 | pmid = 1672392 | doi = 10.1016/0140-6736(91)91371-Z }}</ref>
* low serum [[carnitine]]<ref>{{Cite journal | last = Plioplys | first = A.V. | last2 = Plioplys | first2 = S. | date = 1995 | title = Serum levels of carnitine in chronic fatigue syndrome: clinical correlates|url=https://www.ncbi.nlm.nih.gov/pubmed/8544970|journal=Neuropsychobiology|volume=32|issue=3|pages=132–138|doi=10.1159/000119226|issn=0302-282X|pmid=8544970}}</ref><ref>{{Citation| issn = 1058-4838| volume = 18 | issue =Suppl 1| pages = 62-67| last1 = Kuratsune | first1 = H. | last2 = Yamaguti | first2 = K. | last3 = Takahashi | first3 = M. | last4 = Misaki | first4 = H. | last5 = Tagawa | first5 = S. | last6 = Kitani | first6 = T.| title = Acylcarnitine deficiency in chronic fatigue syndrome| journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = January 1994 | pmid = 8148455}}</ref><ref>{{Citation| doi = 10.1111/j.1468-1331.1995.tb00151.x| issn = 1351-5101| volume = 2 | issue = 5| pages = 425–428| last1 = Majeed | first1 = T. | last2 = de Simone | first2 = C. | last3 = Famularo | first3 = G. | last4 = Marcellini | first4 = S. | last5 = Behan | first5 = P.O. | title = Abnormalities of carnitine metabolism in chronic fatigue syndrome| journal = European Journal of Neurology | date = November 1995 | pmid = 24283722}}</ref>

== Metabolism ==
* Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review<ref>{{Cite journal | last = Tomas | first = Cara | last2 = Newton | first2 = Julia | date = 2018-06-19 | title = Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review | url =https://portlandpress.com/biochemsoctrans/article-abstract/46/3/547/67402/Metabolic-abnormalities-in-chronic-fatigue?redirectedFrom=fulltext|journal=Biochemical Society Transactions|language=en|volume=46|issue=3 | pages = 547–553|doi=10.1042/BST20170503|issn=0300-5127}}</ref>
* Analysis of peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction, supporting a model of deficient ATP production in ME/CFS.<ref name="Sweetman2020">{{Cite journal | last = Sweetman | first = Eiren | authorlink = | last2 = Kleffmann | first2 = Torsten | authorlink2 = | last3 = Edgar | first3 = Christina | authorlink3 = | last4 = de Lange | first4 = Michel | authorlink4 = | last5 = Vallings | first5 = Rosamund | authorlink5 = Rosamund Vallings | last6 = Tate | first6 = Warren | authorlink6 = Warren Tate | date = 2020-09-24 | title = A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction | url =https://doi.org/10.1186/s12967-020-02533-3|journal=Journal of Translational Medicine|volume=18|issue=1 | pages = 365|doi=10.1186/s12967-020-02533-3|issn=1479-5876|pmc = 7512220|pmid=|access-date=|quote=|via=}}</ref>
=== Cellular respiration ===
* abnormalities in [[cellular respiration]] including a reduction in [[glycolysis]],<ref>{{Cite journal | last = Armstrong | first = Christopher W. | last2 = McGregor | first2 = Neil R. | last3 = Lewis | first3 = Donald P. | last4 = Butt | first4 = Henry L. | last5 = Gooley | first5 = Paul R. | date = 2015-05-30 | title = Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients|url=https://link.springer.com/article/10.1007/s11306-015-0816-5 | journal=Metabolomics|language=en | volume=11 | issue=6 | pages=1626–1639 | doi=10.1007/s11306-015-0816-5 | issn=1573-3882}}</ref> including impaired [[pyruvate dehydrogenase]]<ref>{{Cite journal | last = Fluge | first = Øystein | last2 = Mella | first2 = Olav | last3 = Bruland | first3 = Ove | last4 = Risa | first4 = Kristin | last5 = Dyrstad | first5 = Sissel E. | last6 = Alme | first6 = Kine | last7 = Rekeland | first7 = Ingrid G. | last8 = Sapkota | first8 = Dipak | last9 = Røsland | first9 = Gro V. | date = 2016-12-22 | title = Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/28018972 | journal=JCI insight|volume=1 | issue=21 | pages = e89376 | doi=10.1172/jci.insight.89376 | issn=2379-3708 | pmc=5161229 | pmid=28018972}}</ref>
* increased [[lactic acid]]<ref name="Plioplys1995">{{cite journal | last1 = Plioplys | first1 = AV | authorlink1 = | last2 = Plioplys | first2 = S | authorlink2 = | title = Serum levels of carnitine in chronic fatigue syndrome: clinical correlates | journal = Neuropsychobiology | date = 1995 | volume = 32 | issue = 3 | pages = 132-8 | pmid = 8544970 | url = http://www.ncbi.nlm.nih.gov/pubmed/8544970 }}</ref><ref name="LaneRJ1998">{{cite journal | last1 = Lane | first1 = RJ | authorlink1 = | last2 = Barrett | first2 = MC | authorlink2 = Michael Barrett | last3 = Taylor | first3 = DJ | authorlink3 = Doris Taylor | last4 = Kemp | first4 = GJ | authorlink4 = Graham Kemp | last5 = Lodi | first5 = R | authorlink5 = Raffaele Lodi | title = Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle | journal = Neuromuscul Disord | volume = 8 | issue = 3-4 | pages = 204-9 | date = May 1998 | pmid = 9631403 | url = http://www.ncbi.nlm.nih.gov/pubmed/9631403 }}</ref><ref name="JonesDE2010">{{cite journal | last1 = Jones | first1 = David EJ | authorlink1 = | last2 = Hollingsworth | first2 = Kieren G | authorlink2 = Kieren Hollingsworth | last3 = Taylor | first3 = Renee R | authorlink3 = Renee Taylor | last4 = Blamire | first4 = Andrew M | authorlink4 = Andrew Blamire | last5 = Newton | first5 = Julia L | authorlink5 = Julia Newton | title = Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome | journal = J Intern Med | volume = 267 | issue = 4 | pages = 394-401 | date = Apr 2010 | pmid = 20433583 | doi = 10.1111/j.1365-2796.2009.02160.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02160.x/abstract }}</ref><ref name="LengertN2015">{{cite journal | last1 = Lengert | first1 = Nicor | authorlink1 = Nicor Lengert | last2 = Drossel | first2 = Barbara | authorlink2 = Barbara Drossel | title = In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome | journal = Biophysical Chemistry | volume = 202 | pages = 21–31 | date = Jul 2015 | pmid = 25899994 | doi = 10.1016/j.bpc.2015.03.009 | url = http://www.sciencedirect.com/science/article/pii/S0301462215000630 }}</ref><ref name="Mathew2009"/>
* reduction in metabolites reflecting a slowed metabolism<ref>{{Cite journal | last = Naviaux | first = Robert K. | authorlink1 = Robert Naviaux | last2 = Naviaux | first2 = Jane C. | last3 = Li | first3 = Kefeng | last4 = Bright | first4 = A. Taylor | last5 = Alaynick | first5 = William A. | last6 = Wang | first6 = Lin | last7 = Baxter | first7 = Asha | last8 = Nathan | first8 = Neil | last9 = Anderson | first9 = Wayne | date = 2016-09-13 | title = Metabolic features of chronic fatigue syndrome|url=http://www.pnas.org/content/113/37/E5472 | journal=Proceedings of the National Academy of Sciences|language=en | volume=113 | issue=37 | pages = E5472–E5480 | doi=10.1073/pnas.1607571113 | issn=0027-8424 | pmid=27573827}}</ref>
*analysis of peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction, supporting a model...that would suggest an elevation of oxidative stress.<ref name="Sweetman2020" />

=== Exercise ===
* reduced pain threshold<ref name="Whiteside, 2004">{{Cite journal | last1 = Whiteside | first1 = Alan | authorlink1 = | last2 = Hansen | first2 = Stig | authorlink2 = | last3 = Chaudhuri | first3 = Abhijit | authorlink3 = Abhijit Chaudhuri | title = Exercise lowers pain threshold in chronic fatigue syndrome | journal = Pain | volume = 109 | issue = 3 | pages = 497-499 | date = 2004 | pmid = 15157711 | doi = 10.1016/j.pain.2004.02.029 }}</ref>
* translocation of bacteria<ref name="ShuklaS2015">{{cite journal | last1 = Shukla | first1 = Sanjay K | authorlink1 = Sanjay Shukla | last2 = Cook | first2 = Dane | authorlink2 = Dane Cook | last3 = Meyer | first3 = Jacob | authorlink3 = Jacob Meyer | last4 = Vernon | first4 = Suzanne D | authorlink4 = Suzanne Vernon | last5 = Le | first5 = Thao | authorlink5 = Thao Le | last6 = Clevidence | first6 = Derek | authorlink6 = Derek Clevidence | last7 = Robertson | first7 = Charles E | authorlink7 = Charles Robertson | last8 =Schrodi | first8 = Steven J | authorlink8 = Steven Schrodi | last9 = Yale | first9 = Steven | authorlink9 = Steven Yale | last10 = Frank | first10 = Daniel N | authorlink10 = Daniel Frank | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | journal = PLoS ONE | date = Dec 18, 2015 | pmid = 26683192 | doi = 10.1371/journal.pone.0145453 | url = http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145453 }}</ref>
* loss of capacity to recover from acidosis on repeat exercise<ref name="JonesDE2012">{{cite journal | last1 = Jones | first1 = David EJ | authorlink1 = David Jones | last2 = Hollingsworth | first2 = Kieren G | authorlink2 = Kieren Hollingsworth | last3 = Jakovljevic | first3 = Djordje G | authorlink3 = Djordje Jakovljevic | last4 = Fattakhova | first4 = Gulnar | authorlink4 = Gulnar Fattakhova | last5 = Pairman | first5 = Jessie | authorlink5 = Jessie Pairman | last6 = Blamire | first6 = Andrew M | authorlink6 = Andrew Blamire | last7 =Trenell | first7 = Michael I | authorlink7 = Michael Trenell | last8 = Newton | first8 = Julia L | authorlink8 = Julia Newton | title = Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome | journal = Eur J Clin Invest | volume = 42 | issue = 2 | pages = 186-94 | date = 12 Jul 2011 | pmid = 21749371 | doi = 10.1111/j.1365-2362.2011.02567.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2011.02567.x/abstract }}</ref>
* increased expression of sensory, adrenergic and immune genes following [[muscle]] exertion<ref name="LightAR2009">{{cite journal | last1 = Light | first1 = Alan R | authorlink1 = Alan Light | last2 = White | first2 = Andrea T | authorlink2 = | last3 = Hughen | first3 = Ronald W | authorlink3 = | last4 = Light | first4 = Kathleen C | authorlink4 = Kathleen Light | title = Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects | journal = J Pain | volume = 10 | issue = 10 | pages = 1099-112 | date = Jul 31, 2009 | pmid = 19647494 | doi = 10.1016/j.jpain.2009.06.003 | url = http://www.jpain.org/article/S1526-5900(09)00574-4/abstract }}</ref><ref name="LightAR2011">{{citation | last1 = Light | first1 = Alan R | authorlink1 = Alan Light | last2 = Bateman | first2 = Lucinda| authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D | authorlink3 = Daehyun Jo | last4 = Hughen | first4 = Ronald W | authorlink4 = Ronald Hughen | last5 = Vanhaitsma | first5 = TA | authorlink5 = Timothy VanHaitsma | last6 = White | first6 = Andrea T | authorlink6 = Andrea White | last7 =Light | first7 = Kathleen C | authorlink7 = Kathleen Light | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome | journal = J Intern Med | volume = 271 | issue = 1 | pages = 64-81 | date = Jul 13, 2011 | pmid = 21615807 | doi = 10.1111/j.1365-2796.2011.02405.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02405.x/abstract }}</ref><ref name="WhiteAT2012">{{citation | last1 = White | first1 = Andrea T | authorlink1 = Andrea White | last2 = Light | first2 = Alan R | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W | authorlink3 = Ronald Hughen | last4 = VanHaitsma | first4 = Timothy A | authorlink4 = Timothy VanHaitsma | last5 = Light | first5 = Kathleen C | authorlink5 = Kathleen Light | title = Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls | journal = Psychosom Med | volume = 74 | issue = 1 | pages = 46-54 | date = Dec 30, 2011 | pmid = 22210239 | doi = 10.1097/PSY.0b013e31824152ed | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/ }}</ref>
* decreased [[oxygen]] utilization<ref>{{Cite journal | last = Vermeulen | first = Ruud CW | authorlink = Ruud Vermeulen | last2 = Vermeulen van Eck | first2 = Ineke WG| date = 2014 | title = Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome|url=https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-20|journal=Journal of Translational Medicine|language=en|volume=12|issue=1|pages=20|doi=10.1186/1479-5876-12-20|issn=1479-5876|pmc=3903040|pmid=24456560}}</ref>

[[File:Abnormal findings in CFS ME.png|thumb|center|alt=Abnormal findings in Chronic fatigue syndrome and myalgic encephalomyelitis. There is no single biomarker, but tests have found differences in blood flow to the brain, hand grip strength, metabolite and mitochondria abnormalities, reduced heart output, white and red blood cell differences, reduced blood volume, differences in gut bacteria, neuroinflammation, abnormal responses to exercise, and other abnormalities.]]

== See also ==
* [[Myalgic encephalomyelitis]]
* [[List of systematic reviews about ME/CFS]]
* [[:Category:Abnormal findings|Abnormal findings (images)]]

== Learn more ==
* [https://www.mdpi.com/2075-4418/9/2/41 Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (2019)] - original research article
* [http://www.meaction.net/wp-content/uploads/2015/05/ME2FCFS-RESEARCH-SUMMARY-Jamie-Seltzer.pdf #MEAction ME/CFS Research Summary]

==References==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Lists]]

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2023-12-21T06:56:01Z

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__NOTOC__

List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis

2023-12-21T04:00:29Z

JenB:Added CD4 and CD8 findings

[[Myalgic encephalomyelitis]]/[[chronic fatigue syndrome]] is a complex multi-system disease and biological abnormalities in patients have been found affecting multiple bodily systems. No single [[diagnostic biomarker|biomarker]]-based diagnostic test has been validated but patients have a range abnormal physical findings affecting multiple bodily systems.<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012
| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf }}</ref> The CDC states that diagnosing ME/CFS relies on a physical and psychiatric assessment, observations, medical history, clinical interview, and results from a mix of blood and urine tests.<ref name="CDC2020diagnosis">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html | title = Diagnosis of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last = Centers of Disease Control|first = | authorlink = Centers for Disease Control and Prevention | date = 2019-05-15 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|url-status=|access-date=2020-09-26}}</ref>

== Nervous system ==
===Brain ===
{{Main article|Brain}}
*Progressive brain changes<ref name="Shan2016"/>

=== Central nervous system ===
{{Main article |page_name =Central nervous system}}
* increased [[Ventricular system|ventricular]] [[lactate]]<ref name="Mathew2009">{{Cite journal | last = Mathew|first = Sanjay J. | last2 = Mao | first2 = Xiangling | last3 = Keegan | first3 = Kathryn A. | last4 = Levine | first4 = Susan M. | authorlink4 = Susan Levine | last5 = Smith | first5 = Eric L.P. | last6 = Heier | first6 = Linda A. | last7 = Otcheretko | first7 = Viktor | last8 = Coplan | first8 = Jeremy D. | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = Apr 2009 | title = Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: anin vivo3.0 T1H MRS imaging study|url=https://onlinelibrary.wiley.com/doi/full/10.1002/nbm.1315|journal=NMR in Biomedicine|language=en|volume=22|issue=3|pages=251–258|doi=10.1002/nbm.1315|issn=0952-3480}}</ref><ref name="Murrough2010">{{Cite journal | last = Murrough|first = James W. | last2 = Mao | first2 = Xiangling | last3 = Collins | first3 = Katherine A. | last4 = Kelly | first4 = Chris | last5 = Andrade | first5 = Gizely | last6 = Nestadt | first6 = Paul | last7 = Levine | first7 = Susan M. | authorlink7 = Susan Levine | last8 = Mathew | first8 = Sanjay J. | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = Jul 2010 | title = Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder | url =https://www.ncbi.nlm.nih.gov/pubmed/20661876|journal=NMR in Biomedicine|volume=23|issue=6 | pages = 643–650|doi=10.1002/nbm.1512|issn=1099-1492|pmid=20661876}}</ref><ref name="Shungu2012">{{Cite journal | last = Shungu | first = Dikoma C. | authorlink1 = Dikoma Shungu | last2 = Weiduschat | first2 = Nora | last3 = Murrough | first3 = James W. | last4 = Mao | first4 = Xiangling | last5 = Pillemer | first5 = Sarah | last6 = Dyke | first6 = Jonathan P. | last7 = Medow | first7 = Marvin S. | last8 = Natelson | first8 = Benjamin H. | authorlink8 = Benjamin Natelson | last9 = Stewart | first9 = Julian M. | date = Sep 2012 | title = Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology|url=https://www.ncbi.nlm.nih.gov/pubmed/22281935|journal=NMR in biomedicine|volume=25|issue=9|pages=1073–1087|doi=10.1002/nbm.2772|issn=1099-1492|pmc=3896084|pmid=22281935}}</ref><ref name="Natelson2017">{{Cite journal | last = Natelson | first = Benjamin H. | authorlink1 = Benjamin Natelson | last2 = Vu | first2 = Diana | last3 = Coplan | first3 = Jeremy D. | last4 = Mao | first4 = Xiangling | last5 = Blate | first5 = Michelle | last6 = Kang | first6 = Guoxin | last7 = Soto | first7 = Eli | last8 = Kapusuz | first8 = Tolga | last9 = Shungu | first9 = Dikoma C. | authorlink9 = Dikoma Shungu | date = 2017-01-02 | title = Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1280114?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=1|pages=15–20|doi=10.1080/21641846.2017.1280114|issn=2164-1846|pmc=5754037|pmid=29308330}}</ref>
* neuroinflammation<ref name="Nakatomi2014">{{Cite journal | last = Nakatomi|first = Yasuhito | last2 = Mizuno | first2 = Kei | last3 = Ishii | first3 = Akira | last4 = Wada | first4 = Yasuhiro | last5 = Tanaka | first5 = Masaaki | last6 = Tazawa | first6 = Shusaku | last7 = Onoe | first7 = Kayo | last8 = Fukuda | first8 = Sanae | last9 = Kawabe | first9 = Joji | date = 2014-06-01 | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study|url=http://jnm.snmjournals.org/content/55/6/945|journal=Journal of Nuclear Medicine|language=en|volume=55|issue=6 | pages = 945–950|doi=10.2967/jnumed.113.131045|issn=0161-5505|pmid=24665088}}</ref><ref name="Zeineh2014">{{citation | last1 = Zeineh | first1 = Michael M | authorlink1 = Michael Zeineh | last2 = Kang | first2 = James | authorlink2 = James Kang | last3 = Atlas | first3 = Scott W | authorlink3 = Scott Atlas | last4 = Raman | first4 = Mira M | authorlink4 = Mira Raman | last5 = Reiss | first5 = Allan L | authorlink5 = Allan Reiss | last6 =Norris | first6 = Jane L | authorlink6 = Jane Norris | last7 =Valencia | first7 = Ian | authorlink7 = Ian Valencia | last8 =Montoya | first8 = Jose G | authorlink8 = Jose Montoya | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome| journal = Radiology | volume = 274 | issue = 2| pages = 517–526 | date = 2014-10-29| doi = 10.1148/radiol.14141079| url = http://pubs.rsna.org/doi/abs/10.1148/radiol.14141079}}</ref><ref name="Mueller2019">{{Cite journal|url=https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink=Christina Mueller | last2 = Lin | first2 = Joanne C | authorlink2 = Joanne Lin | date = 2019 | doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|url-status=|access-date=2019-01-17 | authorlink3 = Sulaiman Sheriff | authorlink4 = Andrew Maudsley | authorlink5 = Jarred Younger | last3 = Sheriff | last4 = Maudsley | last5 = Younger | first3 = Sulaiman | first4 = Andrew A | first5 = Jarred W|volume=|issue=|pages= | page = |journal=Brain Imaging and Behavior}}</ref><ref name="RamsayAward20190117">{{Cite web|url=http://go.solvecfs.org/webmail/192652/97033877/74d435097e87231f24cffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1 | title = Brain Imaging and Behavior publication from Dr. Jarred Younger’s SMCI Ramsay pilot study supports involvement of neuroinflammation in ME/CFS|website=go.solvecfs.org|access-date=2019-01-17 | date = | last = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
* reduced [[Grey matter|grey]]<ref name="Puri2012">{{Cite journal | last = Puri|first = B K | last2 = Jakeman | first2 = P M | last3 = Agour | first3 = M | last4 = Gunatilake | first4 = K D R | last5 = Fernando | first5 = K A C | last6 = Gurusinghe | first6 = A I | last7 = Treasaden | first7 = I H | last8 = Waldman | first8 = A D | last9 = Gishen | first9 = P | date = Jul 2012 | title = Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study|url=https://www.birpublications.org/doi/full/10.1259/bjr/93889091|journal=The British Journal of Radiology|language=en|volume=85|issue=1015| pages = e270–e273|doi=10.1259/bjr/93889091|issn=0007-1285|pmc=3474083|pmid=22128128}}</ref> and [[white matter]]<ref name="Shan2016">{{Cite journal | last = Shan | first = Zack Y. | authorlink = Zack Shan | last2 = Kwiatek | first2 = Richard | last3 = Burnet | first3 = Richard | last4 = Del Fante | first4 = Peter | last5 = Staines | first5 = Donald R. | last6 = Marshall-Gradisnik | first6 = Sonya M. | last7 = Barnden | first7 = Leighton R. | date = 2016-04-28 | title = Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study|url=https://onlinelibrary.wiley.com/doi/full/10.1002/jmri.25283|journal=Journal of Magnetic Resonance Imaging|language=en|volume=44|issue=5|pages=1301–1311|doi=10.1002/jmri.25283|issn=1053-1807|pmc=5111735|pmid=27123773}}</ref><ref name="Puri2012" />
* [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|widespread metabolite abnormalities]]<ref name="Mueller2019"/>

=== Autonomic nervous system ===
{{Main article |page_name =Autonomic nervous system}}
* Orthostatic intolerance<ref>Gerwin Morris, Michael Maes, see citations 12 through 27 in [http://www.biomedcentral.com/1741-7015/11/205 "Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics"] BMC Medicine, 17 September 2013</ref><ref>{{Cite journal | last = Miwa | first = K | date = Jul 2015 | title = Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle|url=https://www.ncbi.nlm.nih.gov/pubmed/24736946|journal=Heart and Vessels|volume=30|issue=4 | pages = 484–489|via=}}</ref>

=== Peripheral nervous system ===
{{Main article |page_name =Peripheral nervous system}}

== Muscular system ==
{{Main article |page_name =Muscle}}
*[[Mitochondrion|mitochondria]]l abnormalities found via [[muscle biopsy]] including: mitochondrial degeneration,<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref> deletions of mitochondrial DNA,<ref name=":0">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref><ref>{{Cite journal | last = Zhang|first = C. | last2 = Baumer | first2 = A. | last3 = Mackay | first3 = I.R. | last4 = Linnane | first4 = A.W. | last5 = Nagley | first5 = P. | date = Apr 1995 | title = Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/7633428|journal=Human Molecular Genetics|volume=4|issue=4 | pages = 751–754|issn=0964-6906|pmid=7633428}}</ref> the reduction of mitochondrial activity<ref name=":0" />
*Increased urinary [[creatine]] excretion during relapses<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>
*Increased [[creatine kinase]] ([[postviral fatigue syndrome]])
*Persistence of [[enterovirus]]es in muscle tissue<ref name=":1">{{Cite journal | last = Gow|first = J.W. | last2 = Behan | first2 = W. M.H. | last3 = Simpson | first3 = K. | last4 = McGarry | first4 = F. | last5 = Keir | first5 = S. | last6 = Behan | first6 = P.O. | date = 1994-01-01 | title = Studies on Enterovirus in Patients with Chronic Fatigue Syndrome|url=https://academic.oup.com/cid/article-abstract/18/Supplement_1/S126/316946|journal=Clinical Infectious Diseases|language=en|volume=18|issue=Suppl 1|pages=S126–S129|doi=10.1093/clinids/18.Supplement_1.S126|issn=1537-6591}}</ref><ref name=":2">{{Cite journal | last = Cunningham|first = Louise | last2 = Bowles | first2 = N.E. | last3 = Lane | first3 = R. J.M. | last4 = Dubowitz | first4 = V. | last5 = Archard | first5 = L.C. | date = 1990 | title = Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-71-6-1399|journal=Journal of General Virology|volume=71|issue=6|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399}}</ref><ref name=":3">{{Cite journal | last = Archard | first = LC | last2 = Bowles | first2 = NE | last3 = Behan | first3 = PO | last4 = Bell | first4 = EJ | last5 = Doyle | first5 = D | date = 1988-06-01 | title = Postviral Fatigue Syndrome: Persistence of Enterovirus RNA in Muscle and Elevated Creatine Kinase, Postviral Fatigue Syndrome: Persistence of Enterovirus RNA in Muscle and Elevated Creatine Kinase|url=https://doi.org/10.1177/014107688808100608|journal=Journal of the Royal Society of Medicine|language=en|volume=81|issue=6 | pages = 326–329|doi=10.1177/014107688808100608|issn=0141-0768|pmc=1291623|pmid=3404526}}</ref><ref name=":4">{{Cite journal | last = Gow|first = J.W. | last2 = Behan | first2 = W.M. | last3 = Clements | first3 = G.B. | last4 = Woodall | first4 = C. | last5 = Riding | first5 = M. | last6 = Behan | first6 = P.O. | date = 1991-03-23 | title = Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome.|url=https://www.bmj.com/content/302/6778/692|journal=BMJ|language=en|volume=302|issue=6778 | pages = 692–696|doi=10.1136/bmj.302.6778.692|issn=0959-8138|pmid=1850635}}</ref>
*abnormalities of [[AMPK]] activation and glucose uptake in cultured skeletal muscle cells<ref name="BrownAE2015">{{Citation | last1 = Brown | first1 = Audrey E | authorlink1 = Audrey Brown | last2 = Jones | first2 = David E | authorlink2 = David Jones | last3 = Walker | first3 = Mark | authorlink3 = Mark Walker | last4 = Newton | first4 = Julia L | authorlink4 = Julia Newton | title = Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells | journal = PLoS One | volume = 10 | issue = 4 | date = 2 Apr 2015 | pmid = 25836975 | doi = 10.1371/journal.pone.0122982 | url = http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982 }}</ref><ref name="Wellness20150420">{{citation | last1 = Dobberstein | first1 = Linda J. | authorlink1 = | title = Master Enzyme Switch Deactivated In Chronic Fatigue Syndrome and Fibromyalgia | journal = Wellness Resources | date = 20 Apr 2015 | url = http://www.wellnessresources.com/health/articles/master_enzyme_switch_deactivated_in_chronic_fatigue_syndrome_and_fibromyalg/ }}</ref>

== Immune system ==
{{Main article |page_name =Immune system}}
=== Immune dysregulation ===
* [[Natural killer cell]] function is reduced<ref>{{Cite journal | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis|url=http://www.ncbi.nlm.nih.gov/pubmed/24343819|journal=International Immunology | date = Apr 2014|issn=1460-2377|pmid=24343819|pages=233–242|volume=26|issue=4|doi=10.1093/intimm/dxt068|first = Ekua Weba | last = Brenu | first2 = Teilah K. | last2 = Huth | first3 = Sharni L. | last3 = Hardcastle | first4 = Kirsty | last4 = Fuller | first5 = Manprit | last5 = Kaur | first6 = Samantha | last6 = Johnston | first7 = Sandra B. | last7 = Ramos | first8 = Don R. | last8 = Staines | first9 = Sonya M. | last9 = Marshall-Gradisnik}}</ref><ref>{{Cite journal | last = Victoria Scott | first = David Strayer | date = 2015 | title=Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity|url=https://www.omicsonline.org/open-access/low-nk-cell-activity-in-chronic-fatigue-syndrome-cfs-and-relationship-to-symptom-severity-2155-9899-1000348.php?aid=59415|journal=Journal of Clinical & Cellular Immunology|language=en|volume=6|issue=4|doi=10.4172/2155-9899.1000348|issn=2155-9899}}</ref>
* [[Cytokine]] dysregulation<ref name="Montoya, 2017">{{citation | last1 = Montoya | first1 = Jose G. | authorlink1 = Jose Montoya | last2 = Holmes | first2 = Tyson H. | authorlink2 = | last3 = Anderson | first3 = Jill N. | authorlink3 = | last4 = Maecker | first4 = Holden T. | authorlink4 = | last5 = Rosenberg-Hasson | first5 = Yael | authorlink5 = | last6 = Valencia | first6 = Ian J. | authorlink6 = | last7 = Chu | first7 = Lily | authorlink7 = Lily Chu | last8 =Younger | first8 = Jarred W. | authorlink8 = Jarred Younger | last9 =Tato | first9 = Cristina M. | authorlink9 = | last10 = Davis | first10 = Mark M. | authorlink10 = Mark Davis | title = Cytokine signature associated with disease severity in chronic fatigue syndrome patients | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 34 | pages = E7150-E7158 | date = 2017 | pmid = | doi = 10.1073/pnas.1710519114 }}</ref><ref>[http://www.meaction.net/2015/12/07/study-finds-evidence-of-downregulated-immune-system-in-mecfs-patients Study finds evidence of downregulated immune system in ME/CFS patients - MEAction - Landi, et al.]</ref><ref>[http://microbediscovery.org/2017/04/04/new-research-discovers-evidence-of-atypical-classical-mecfs/ New Research Discovers Evidence of Atypical & Classical ME/CFS - The Microbe Discovery Project - Apr 4, 2017]</ref>
* Elevated [[regulatory T cell]]s<ref>{{Cite journal | last = Brenu|first = Ekua Weba | last2 = Huth | first2 = Teilah K. | last3 = Hardcastle | first3 = Sharni L. | last4 = Fuller | first4 = Kirsty | last5 = Kaur | first5 = Manprit | last6 = Johnston | first6 = Samantha | last7 = Ramos | first7 = Sandra B. | last8 = Staines | first8 = Don R. | last9 = Marshall-Gradisnik | first9 = Sonya M. | date = Apr 2014 | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis|url=http://www.ncbi.nlm.nih.gov/pubmed/24343819|journal=International Immunology|volume=26|issue=4|pages=233–242|doi=10.1093/intimm/dxt068|issn=1460-2377|pmid=24343819}}</ref>
* increased [[mast cell]] populations<ref>{{Cite journal | last = Rönnberg|first = E | last2 = Calounova | first2 = G | last3 = Pejler | first3 = G | date = June 2017 | title = Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients|url=https://www.ncbi.nlm.nih.gov/pubmed/27362406|journal=Asian Pac J Allergy Immunol|volume=35|issue=2 | pages = 75-81|via=}}</ref>
* elevated anti-cholinergic [[Muscarinic acetylcholine receptor|muscarinic]], Β-adrenergic,<ref>{{Cite journal | last = Loebel|first = Madlen | last2 = Grabowski | first2 = Patricia | last3 = Heidecke | first3 = Harald | last4 = Bauer | first4 = Sandra | last5 = Hanitsch | first5 = Leif G. | last6 = Wittke | first6 = Kirsten | last7 = Meisel | first7 = Christian | last8 = Reinke | first8 = Petra | last9 = Volk | first9 = Hans-Dieter | date = Feb 2016 | title = Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26399744|journal=Brain, Behavior, and Immunity|volume=52 | pages = 32–39|doi=10.1016/j.bbi.2015.09.013|issn=1090-2139|pmid=26399744}}</ref> [[phosphatidylinositol]]<ref>{{Cite journal | last = Maes | first = Michael | last2 = Mihaylova | first2 = Ivanka | last3 = Leunis | first3 = Jean-Claude | date = Dec 2007 | title = Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression | url =https://www.ncbi.nlm.nih.gov/pubmed/18063934|journal=Neuro Endocrinology Letters|volume=28|issue=6 | pages = 861–867|issn=0172-780X|pmid=18063934}}</ref> and [[serotonin]]<ref>{{Cite journal | last = Maes | first = Michael | last2 = Ringel | first2 = Karl | last3 = Kubera | first3 = Marta | last4 = Anderson | first4 = George | last5 = Morris | first5 = Gerwyn | last6 = Galecki | first6 = Piotr | last7 = Geffard | first7 = Michel | date = 2013-09-05 | title = In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation | url =https://www.ncbi.nlm.nih.gov/pubmed/23664637|journal=Journal of Affective Disorders|volume=150|issue=2|pages=223–230|doi=10.1016/j.jad.2013.03.029|issn=1573-2517|pmid=23664637}}</ref> autoantibodies
* Reduced CD4+ function<ref name=":5">{{Cite journal|title=Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations|date=2020-03-02|url=https://pubmed.ncbi.nlm.nih.gov/31830003/|journal=The Journal of Clinical Investigation|volume=130|issue=3|pages=1491–1505|last=Mandarano|first=Alexandra H.|last2=Maya|first2=Jessica|last3=Giloteaux|first3=Ludovic|last4=Peterson|first4=Daniel L.|last5=Maynard|first5=Marco|last6=Gottschalk|first6=C. Gunnar|last7=Hanson|first7=Maureen R.|doi=10.1172/JCI132185|pmc=7269566|pmid=31830003|issn=1558-8238}}</ref> and reduced CD4+ count<ref name=":6">{{Cite journal|title=Study of immune alterations in patients with chronic fatigue syndrome with different etiologies|date=2004|url=https://pubmed.ncbi.nlm.nih.gov/15345193/|journal=International Journal of Immunopathology and Pharmacology|volume=17|issue=2 Suppl|pages=57–62|last=Racciatti|first=D.|last2=Dalessandro|first2=M.|last3=Delle Donne|first3=L.|last4=Falasca|first4=K.|last5=Zingariello|first5=P.|last6=Paganelli|first6=R.|last7=Pizzigallo|first7=E.|last8=Vecchiet|first8=J.|doi=10.1177/03946320040170S210|pmid=15345193|issn=0394-6320}}</ref>
* Reduced CD8+ function<ref name=":5" /> and reduced CD8+ count<ref name=":6" />

=== Chronic infection ===
* [[Enterovirus]]: Persistence of [[enterovirus]]es in muscle tissue;<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> brain;<ref name="McGarry19942">{{citation | last1 = McGarry | first1 = Frances | author-link1 = Frances McGarry | last2 = Gow | first2 = John | authorlink2 = John Gow | last3 = Behan | first3 = Peter O | authorlink3 = Peter O Behan | title = Enterovirus in the Chronic Fatigue Syndrome | journal = Annals of Internal Medicine | volume = 120 | issue = 11| pages = 972–973 | date = Jun 1, 1994 | doi = 10.7326/0003-4819-120-11-199406010-00020 | url = http://www.ncbi.nlm.nih.gov/pubmed/8172448 }}</ref> and gut;<ref name="ChiaJKS2016">{{Cite journal | last1 = Chia | first1 = JKS | authorlink1 = John Chia | last2 = Chia | first2 = AY | authorlink2 = Andrew Chia | title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach | journal = Journal of Clinical Pathology | volume = 61 | issue = 1| pages = 43–48 | date = Jan 1, 2008 | pmid = 17872383 | doi = 10.1136/jcp.2007.050054 | url = http://jcp.bmj.com/content/61/1/43 }}</ref> increased detection of viral [[RNA]] via PCR; increased [[:Category:Antibodies|antibodies]]
* [[Herpesvirus]]{{citation needed}}

== Lymphatic system ==

== Cardiovascular system ==

{{Main article|page_name =Cardiovascular system}}{{Main article|page_name =Cardiac problems in ME/CFS}}

=== Heart ===
* Smaller than normal [[left ventricle]] of the [[heart]],<ref name=":8">Miwa K., [http://www.ncbi.nlm.nih.gov/pubmed/24736946 "Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle"] Heart Vessels, July 2015</ref><ref>Hollingsworth K.G [http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1365-2796.2011.02429.x/ "Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging"] J Intern Med 2012; 271: 264–270.</ref><ref name="Olimulder, 2016">{{Cite journal | last1 = Olimulder | first1 = M.A.G.M. | authorlink1 = | last2 = Galjee | first2 = M.A. | authorlink2 = | last3 = Wagenaar | first3 = L.J. | authorlink3 = | last4 = van Es | first4 = J. | authorlink4 = | last5 = van der Palen | first5 = J. | authorlink5 = | last6 = Visser | first6 = F.C. | authorlink6 = | last7 =Vermeulen | first7 = R.C.W. | authorlink7 = | last8 = von Birgelen | first8 = C. | authorlink8 = | title = Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging | journal = Netherlands Heart Journal | volume = 24 | pages = 709–716 | date = 2016 | url = https://link.springer.com/article/10.1007/s12471-016-0885-8 | doi = 10.1007/s12471-016-0885-8 }}</ref><ref>[http://openheart.bmj.com/content/3/1/e000381.long Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study]</ref> [[small heart syndrome]],<ref name=":8" /> and low [[Cardiovascular system|cardiac]] output.<ref>Miwa K., Fujita M., [http://www.ncbi.nlm.nih.gov/pubmed/19881233 "Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome"] Intern Med, 2009;48(21):1849-54</ref>
* Mean age of death from heart failure of [[chronic fatigue syndrome|CFS]] patients is 58.7 years as compared to 83.1 years for the general population.<ref>Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S, [http://www.ncbi.nlm.nih.gov/pubmed/16844674 "Causes of death among patients with chronic fatigue syndrome"] Health Care Women Int., 27(7): 615-626. 2006</ref>
=== Circulation ===
* reduced blood flow to the [[Brain|brain,]]<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 = Benjamin | authorlink1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | last3 = Stegner | first3 = Aaron J | last4 = Lange | first4 = Gudrun | authorlink4 = Gudrun Lange | last5 = Vu | first5 = Diana | last6 = Blate | first6 = Michelle | last7 = Kang | first7 = Guoxin | last8 = Soto | first8 = Eli | last9 = Kapusuz | first9 = Tolga | last10 = Shungu | first10 = Dikoma C | authorlink10 = Dikoma Shungu | title=Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | date = 2017 | journal=Journal of the Neurological Sciences|volume=375|issue= | page = 411-416|doi=10.1016/j.jns.2017.02.046|pmid=|quote=}}</ref><ref name=":32">{{Cite journal | last = Costa|first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8542261|journal=QJM: monthly journal of the Association of Physicians|volume=88|issue=11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name=":10">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Del Fante | first8 = Peter | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692|journal=NMR in Biomedicine|language=en|volume=24|issue=10|pages=1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc = 4369126|pmid=21560176}}</ref><ref>{{Cite journal | last = Biswal|first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | authorlink1 = Benjamin Natelson | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666|journal=Journal of the Neurological Sciences|volume=301|issue=1 | pages = 9–11 |doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name=":11">{{Cite journal | last = Yoshiuchi|first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | authorlink3 = Benjamin Natelson | date = 2006 | title=Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x|journal=Clinical Physiology and Functional Imaging|language=en|volume=26|issue=2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.|url=http://europepmc.org/abstract/med/1491843|journal=Nuclear medicine communications|volume=13|issue=10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao|first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://cvi.asm.org/content/1/2/222|journal=Clinical and Diagnostic Laboratory Immunology|language=en|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome|url=http://www.sciencedirect.com/science/article/pii/S0002934398001752|journal=The American Journal of Medicine|volume=105|issue=3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref> even in the absence of [[Postural orthostatic tachycardia syndrome|POTS]]/[[Neurally mediated hypotension|NMH]]<ref>{{Citation | title = CMRC Conference 2017 day 1- Prof Dr Frans Visser |url =https://www.youtube.com/watch?v=IWRA23D_MUg|language=en|access-date=2019-09-03}}</ref>
* reduced blood flow to the heart<ref>{{Cite journal | last = Patrick Neary|first = J. | last2 = Roberts | first2 = Andy D.W. | last3 = Leavins | first3 = Nina | last4 = Harrison | first4 = Michael F. | last5 = Croll | first5 = James C. | last6 = Sexsmith | first6 = James R. | date = Nov 2008 | title = Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1475-097X.2008.00822.x|journal=Clinical Physiology and Functional Imaging|volume=28|issue=6 | pages = 364–372|doi=10.1111/j.1475-097x.2008.00822.x|issn=1475-0961}}</ref><ref>{{Cite journal | last = Peterson | first = PK | last2 = Sirr | first2 = SA | last3 = Grammith | first3 = FC | last4 = Schenck | first4 = CH | last5 = Pheley | first5 = AM | last6 = Hu | first6 = S | last7 = Chao | first7 = C C | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC368231/|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
*peripheral endothelial dysfunction, which is an established risk factor for cardiovascular disease<ref name="endothelial2020">{{Cite journal | last = Scherbakov|first = Nadja | authorlink = | last2 = Szklarski | first2 = Marvin | author-link2 = | last3 = Hartwig | first3 = Jelka | author-link3 = | last4 = Sotzny | first4 = Franziska | author-link4 = Franziska Sotzny | last5 = Lorenz | first5 = Sebastian | author-link5 = | last6 = Meyer | first6 = Antje | authorlink6 = Antje Meyer | last7 = Grabowski | first7 = Patricia | last8 = Doehner | first8 = Wolfram | last9 = Scheibenbogen | first9 = Carmen | authorlink9 = Carmen Scheibenbogen | date = 2020 | title=Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ehf2.12633|journal=ESC Heart Failure|language=en|volume=7|issue=3|pages=1064–1071|doi=10.1002/ehf2.12633|issn=2055-5822|pmc = 7261521|pmid=32154656|access-date=|quote=|via=}}</ref>

=== Blood vessels ===

=== Blood ===
{{Main article|Brain}}
* reduced [[blood]] volume<ref>{{Cite journal | last = Hurwitz|first = BE | last2 = Coryell | first2 = VT | last3 = Parker | first3 = M | last4 = Martin | first4 = P | last5 = LaPerriere .... | first5 = A | last6 = Bilsker | first6 = MS | date = | title = Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function | url =http://www.clinsci.org/content/118/2/125|journal=Clinical Science|volume=118|issue=2|pages=125-135|via=}}</ref><ref>{{Cite journal | last = Streeten | first = DHP | last2 = Bell | first2 = D | date = 1998 | title=Circulating Blood Volume in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n01_02|journal=Journal of Chronic Fatigue Syndrome|volume=4 | pages = 3-11|via=}}</ref>
* abnormally shaped of [[Red blood cell|red blood cells]]<ref name="Simpson1989">{{Citation | last1 = Simpson | first1 = LO | authorlink1 = Leslie Simpson | title = Nondiscocytic erythrocytes in myalgic encephalomyelitis | journal = The New Zealand Medical Journal | volume = 102 | issue = 864 | pages = 126-127 | date = 1989 | pmid = 2927808 | doi = }}</ref><ref>{{Cite journal | last = Richards | first = RS | last2 = Wang | first2 = L | last3 = Jelinek | first3 = H | date = Jan 2007 | title = Erythrocyte oxidative damage in chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/pii/S0188440906002992|journal=Archives of Medical Research|volume=38|issue=1 | pages = 94-98|via=}}</ref>
* reduced oxygen uptake in [[hemoglobin]]<ref>{{Cite journal | last = Miller | first = Ruth R | last2 = Reid | first2 = W Darlene | last3 = Mattman | first3 = Andre | last4 = Yamabayashi | first4 = Cristiane | last5 = Steiner | first5 = Theodore | last6 = Parker | first6 = Shoshana | last7 = Gardy | first7 = Jennifer | last8 = Tang | first8 = Patrick | last9 = Patrick | first9 = David M | date = 2015-05-20 | title = Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case–control study|url=http://doi.org/10.1186/s12967-015-0527-8|journal=Journal of Translational Medicine|language=en|volume=13|issue=1|doi=10.1186/s12967-015-0527-8|issn=1479-5876|pmc=4438583|pmid=25990639}}</ref>

== Digestive system ==

=== Gastrointestinal tract ===
{{Main article |page_name = Gastrointestinal tract}}
* lower levels of [[Bifidobacteria]], [[Escherichia coli]] and higher levels of [[aerobic bacteria]],<ref>{{Cite journal | title = Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value|url=http://www.medical-hypotheses.com/article/S0306-9877(03)00096-3/abstract|journal=Medical Hypotheses | date = Jun 2003|issn=0306-9877 | pages = 915–923|volume=60|issue=6|doi=10.1016/S0306-9877(03)00096-3|language=English|first = Alan C | last = Logan | first2 = A | last2 = Venket Rao | first3 = Dinaz | last3 = Irani}}</ref> in particular [[Enterococcus]] and [[Streptococcus]] species<ref>{{Cite journal | title = Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome|url=http://www.ncbi.nlm.nih.gov/pubmed/19567398|journal=In Vivo (Athens, Greece) | date = Jul 2009|issn=0258-851X|pmid=19567398 | pages = 621–628|volume=23|issue=4|first = John R. | last = Sheedy | first2 = Richard E.H. | last2 = Wettenhall | first3 = Denis | last3 = Scanlon | first4 = Paul R. | last4 = Gooley | first5 = Donald P. | last5 = Lewis | first6 = Neil | last6 = McGregor | first7 = David I. | last7 = Stapleton | first8 = Henry L. | last8 = Butt | first9 = Kenny L. | last9 = DE Meirleir}}</ref>
* higher levels of enterococcus bacteria in CFS patients were associated with more severe neurological and cognitive dysfunction<ref>https://getinfo.de/en/search/id/BLCP%3ACN055885616/%60Bacterial-Colonosis-in-Patients-with-Persistent/</ref>
* Significantly increased proportions of Firmicutes<ref>{{Cite journal | title = High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients|url=https://www.sciencedirect.com/science/article/pii/S1075996413000929|journal=Anaerobe | date = 2013-08-01|issn=1075-9964 | pages = 50–56|volume=22|doi=10.1016/j.anaerobe.2013.06.002|language=en}}</ref><ref name=":7">{{Cite journal | last = Giloteaux | first = Ludovic | last2 = Goodrich | first2 = Julia K. | last3 = Walters | first3 = William A. | last4 = Levine | first4 = Susan M. | author-link4 = Susan Levine | last5 = Ley | first5 = Ruth E. | last6 = Hanson | first6 = Maureen R. | date = 2016-06-23 | title = Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918027/|journal=Microbiome|volume=4|doi=10.1186/s40168-016-0171-4|issn=2049-2618|pmc=4918027|pmid=27338587}}</ref> and Bacteroides<ref name=":7" />
* CFS patients may suffer from [[small intestinal bacterial overgrowth]] (SIBO) at high rates<ref name="Pimentel2000">{{Citation | last1 = Pimentel | first1 = M | authorlink1 = Mark Pimentel | last2 = Hallegua | first2 = D | authorlink2 = David Hallegua | last3 = Chow | first3 = EJ | authorlink3 = Evelyn Chow | last4 = Wallace | first4 = D | authorlink4 = Daniel Wallace | last5 = Bonorris | first5 = G | authorlink5 = George Bonorris | last6 = Lin | first6 = HC | authorlink6 = Henry Lin | title = Eradication of small intestinal bacterial overgrowth decreases symptoms in chronic fatigue syndrome: A double blind, randomized study | journal = Gastroenterology | volume = 118 | issue = 4| pages = 414 | date = 1 Apr 2000 | doi = 10.1016/S0016-5085(00)83765-8 | url = http://www.gastrojournal.org/article/S0016508500837658/abstract }}</ref>
* Higher levels of serum [[Immunoglobulin A|IgA]] and [[Immunoglobulin M|IgM]] against [[lipopolysaccharide]]s (LPS), a major component of the outer membrane of [[gram-negative bacteria]], indicating translocation.<ref>{{Cite journal | last = Maes | first = Michael | last2 = Mihaylova | first2 = Ivana | last3 = Leunis | first3 = Jean-Claude | date = 2007-04-01 | title = Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): Indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut–intestinal permeability|url=http://www.sciencedirect.com/science/article/pii/S0165032706003557|journal=Journal of Affective Disorders|language=en|volume=99|issue=1|pages=237–240|doi=10.1016/j.jad.2006.08.021|issn=0165-0327}}</ref> Serum [[Immunoglobulin A|IgA]] was significantly correlated to the severity of illness.

=== Liver ===
* Reduced [[liver]] volume<ref>{{Cite journal | title = Liver volume is lower and associates with resting and dynamic blood pressure variability in chronic fatigue syndrome|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1488525|journal=Fatigue: Biomedicine, Health & Behavior | date = 2018-06-18|issn=2164-1846|pages=141–152|volume=6|issue=3|doi=10.1080/21641846.2018.1488525|language=en | first = Pawel | last = Zalewski | first2 = Andreas | last2 = Finkelmeyer | first3 = James | last3 = Frith | first4 = Laura | last4 = Maclachlan | first5 = Andrew | last5 = Blamire | first6 = Julia L. | last6 = Newton}}</ref>

== Nutrition ==
* low red blood cell [[magnesium]]<ref name="cfs_and_blood_mg">{{Citation | last1 = I.M. | first1 = Cox | authorlink1 = | last2 = M.J. | first2 = Campbell | authorlink2 = | last3 = D. |first3 = Dowson | authorlink3 = | title = Red blood cell magnesium and chronic fatigue syndrome | journal = The Lancet
| year = 1991 | pmid = 1672392 | doi = 10.1016/0140-6736(91)91371-Z }}</ref>
* low serum [[carnitine]]<ref>{{Cite journal | last = Plioplys | first = A.V. | last2 = Plioplys | first2 = S. | date = 1995 | title = Serum levels of carnitine in chronic fatigue syndrome: clinical correlates|url=https://www.ncbi.nlm.nih.gov/pubmed/8544970|journal=Neuropsychobiology|volume=32|issue=3|pages=132–138|doi=10.1159/000119226|issn=0302-282X|pmid=8544970}}</ref><ref>{{Citation| issn = 1058-4838| volume = 18 | issue =Suppl 1| pages = 62-67| last1 = Kuratsune | first1 = H. | last2 = Yamaguti | first2 = K. | last3 = Takahashi | first3 = M. | last4 = Misaki | first4 = H. | last5 = Tagawa | first5 = S. | last6 = Kitani | first6 = T.| title = Acylcarnitine deficiency in chronic fatigue syndrome| journal = Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America | date = January 1994 | pmid = 8148455}}</ref><ref>{{Citation| doi = 10.1111/j.1468-1331.1995.tb00151.x| issn = 1351-5101| volume = 2 | issue = 5| pages = 425–428| last1 = Majeed | first1 = T. | last2 = de Simone | first2 = C. | last3 = Famularo | first3 = G. | last4 = Marcellini | first4 = S. | last5 = Behan | first5 = P.O. | title = Abnormalities of carnitine metabolism in chronic fatigue syndrome| journal = European Journal of Neurology | date = November 1995 | pmid = 24283722}}</ref>

== Metabolism ==
* Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review<ref>{{Cite journal | last = Tomas | first = Cara | last2 = Newton | first2 = Julia | date = 2018-06-19 | title = Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review | url =https://portlandpress.com/biochemsoctrans/article-abstract/46/3/547/67402/Metabolic-abnormalities-in-chronic-fatigue?redirectedFrom=fulltext|journal=Biochemical Society Transactions|language=en|volume=46|issue=3 | pages = 547–553|doi=10.1042/BST20170503|issn=0300-5127}}</ref>
* Analysis of peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction, supporting a model of deficient ATP production in ME/CFS.<ref name="Sweetman2020">{{Cite journal | last = Sweetman | first = Eiren | authorlink = | last2 = Kleffmann | first2 = Torsten | authorlink2 = | last3 = Edgar | first3 = Christina | authorlink3 = | last4 = de Lange | first4 = Michel | authorlink4 = | last5 = Vallings | first5 = Rosamund | authorlink5 = Rosamund Vallings | last6 = Tate | first6 = Warren | authorlink6 = Warren Tate | date = 2020-09-24 | title = A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction | url =https://doi.org/10.1186/s12967-020-02533-3|journal=Journal of Translational Medicine|volume=18|issue=1 | pages = 365|doi=10.1186/s12967-020-02533-3|issn=1479-5876|pmc = 7512220|pmid=|access-date=|quote=|via=}}</ref>
=== Cellular respiration ===
* abnormalities in [[cellular respiration]] including a reduction in [[glycolysis]],<ref>{{Cite journal | last = Armstrong | first = Christopher W. | last2 = McGregor | first2 = Neil R. | last3 = Lewis | first3 = Donald P. | last4 = Butt | first4 = Henry L. | last5 = Gooley | first5 = Paul R. | date = 2015-05-30 | title = Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients|url=https://link.springer.com/article/10.1007/s11306-015-0816-5 | journal=Metabolomics|language=en | volume=11 | issue=6 | pages=1626–1639 | doi=10.1007/s11306-015-0816-5 | issn=1573-3882}}</ref> including impaired [[pyruvate dehydrogenase]]<ref>{{Cite journal | last = Fluge | first = Øystein | last2 = Mella | first2 = Olav | last3 = Bruland | first3 = Ove | last4 = Risa | first4 = Kristin | last5 = Dyrstad | first5 = Sissel E. | last6 = Alme | first6 = Kine | last7 = Rekeland | first7 = Ingrid G. | last8 = Sapkota | first8 = Dipak | last9 = Røsland | first9 = Gro V. | date = 2016-12-22 | title = Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/28018972 | journal=JCI insight|volume=1 | issue=21 | pages = e89376 | doi=10.1172/jci.insight.89376 | issn=2379-3708 | pmc=5161229 | pmid=28018972}}</ref>
* increased [[lactic acid]]<ref name="Plioplys1995">{{cite journal | last1 = Plioplys | first1 = AV | authorlink1 = | last2 = Plioplys | first2 = S | authorlink2 = | title = Serum levels of carnitine in chronic fatigue syndrome: clinical correlates | journal = Neuropsychobiology | date = 1995 | volume = 32 | issue = 3 | pages = 132-8 | pmid = 8544970 | url = http://www.ncbi.nlm.nih.gov/pubmed/8544970 }}</ref><ref name="LaneRJ1998">{{cite journal | last1 = Lane | first1 = RJ | authorlink1 = | last2 = Barrett | first2 = MC | authorlink2 = Michael Barrett | last3 = Taylor | first3 = DJ | authorlink3 = Doris Taylor | last4 = Kemp | first4 = GJ | authorlink4 = Graham Kemp | last5 = Lodi | first5 = R | authorlink5 = Raffaele Lodi | title = Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle | journal = Neuromuscul Disord | volume = 8 | issue = 3-4 | pages = 204-9 | date = May 1998 | pmid = 9631403 | url = http://www.ncbi.nlm.nih.gov/pubmed/9631403 }}</ref><ref name="JonesDE2010">{{cite journal | last1 = Jones | first1 = David EJ | authorlink1 = | last2 = Hollingsworth | first2 = Kieren G | authorlink2 = Kieren Hollingsworth | last3 = Taylor | first3 = Renee R | authorlink3 = Renee Taylor | last4 = Blamire | first4 = Andrew M | authorlink4 = Andrew Blamire | last5 = Newton | first5 = Julia L | authorlink5 = Julia Newton | title = Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome | journal = J Intern Med | volume = 267 | issue = 4 | pages = 394-401 | date = Apr 2010 | pmid = 20433583 | doi = 10.1111/j.1365-2796.2009.02160.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02160.x/abstract }}</ref><ref name="LengertN2015">{{cite journal | last1 = Lengert | first1 = Nicor | authorlink1 = Nicor Lengert | last2 = Drossel | first2 = Barbara | authorlink2 = Barbara Drossel | title = In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome | journal = Biophysical Chemistry | volume = 202 | pages = 21–31 | date = Jul 2015 | pmid = 25899994 | doi = 10.1016/j.bpc.2015.03.009 | url = http://www.sciencedirect.com/science/article/pii/S0301462215000630 }}</ref><ref name="Mathew2009"/>
* reduction in metabolites reflecting a slowed metabolism<ref>{{Cite journal | last = Naviaux | first = Robert K. | authorlink1 = Robert Naviaux | last2 = Naviaux | first2 = Jane C. | last3 = Li | first3 = Kefeng | last4 = Bright | first4 = A. Taylor | last5 = Alaynick | first5 = William A. | last6 = Wang | first6 = Lin | last7 = Baxter | first7 = Asha | last8 = Nathan | first8 = Neil | last9 = Anderson | first9 = Wayne | date = 2016-09-13 | title = Metabolic features of chronic fatigue syndrome|url=http://www.pnas.org/content/113/37/E5472 | journal=Proceedings of the National Academy of Sciences|language=en | volume=113 | issue=37 | pages = E5472–E5480 | doi=10.1073/pnas.1607571113 | issn=0027-8424 | pmid=27573827}}</ref>
*analysis of peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction, supporting a model...that would suggest an elevation of oxidative stress.<ref name="Sweetman2020" />

=== Exercise ===
* reduced pain threshold<ref name="Whiteside, 2004">{{Cite journal | last1 = Whiteside | first1 = Alan | authorlink1 = | last2 = Hansen | first2 = Stig | authorlink2 = | last3 = Chaudhuri | first3 = Abhijit | authorlink3 = Abhijit Chaudhuri | title = Exercise lowers pain threshold in chronic fatigue syndrome | journal = Pain | volume = 109 | issue = 3 | pages = 497-499 | date = 2004 | pmid = 15157711 | doi = 10.1016/j.pain.2004.02.029 }}</ref>
* translocation of bacteria<ref name="ShuklaS2015">{{cite journal | last1 = Shukla | first1 = Sanjay K | authorlink1 = Sanjay Shukla | last2 = Cook | first2 = Dane | authorlink2 = Dane Cook | last3 = Meyer | first3 = Jacob | authorlink3 = Jacob Meyer | last4 = Vernon | first4 = Suzanne D | authorlink4 = Suzanne Vernon | last5 = Le | first5 = Thao | authorlink5 = Thao Le | last6 = Clevidence | first6 = Derek | authorlink6 = Derek Clevidence | last7 = Robertson | first7 = Charles E | authorlink7 = Charles Robertson | last8 =Schrodi | first8 = Steven J | authorlink8 = Steven Schrodi | last9 = Yale | first9 = Steven | authorlink9 = Steven Yale | last10 = Frank | first10 = Daniel N | authorlink10 = Daniel Frank | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | journal = PLoS ONE | date = Dec 18, 2015 | pmid = 26683192 | doi = 10.1371/journal.pone.0145453 | url = http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145453 }}</ref>
* loss of capacity to recover from acidosis on repeat exercise<ref name="JonesDE2012">{{cite journal | last1 = Jones | first1 = David EJ | authorlink1 = David Jones | last2 = Hollingsworth | first2 = Kieren G | authorlink2 = Kieren Hollingsworth | last3 = Jakovljevic | first3 = Djordje G | authorlink3 = Djordje Jakovljevic | last4 = Fattakhova | first4 = Gulnar | authorlink4 = Gulnar Fattakhova | last5 = Pairman | first5 = Jessie | authorlink5 = Jessie Pairman | last6 = Blamire | first6 = Andrew M | authorlink6 = Andrew Blamire | last7 =Trenell | first7 = Michael I | authorlink7 = Michael Trenell | last8 = Newton | first8 = Julia L | authorlink8 = Julia Newton | title = Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome | journal = Eur J Clin Invest | volume = 42 | issue = 2 | pages = 186-94 | date = 12 Jul 2011 | pmid = 21749371 | doi = 10.1111/j.1365-2362.2011.02567.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2011.02567.x/abstract }}</ref>
* increased expression of sensory, adrenergic and immune genes following [[muscle]] exertion<ref name="LightAR2009">{{cite journal | last1 = Light | first1 = Alan R | authorlink1 = Alan Light | last2 = White | first2 = Andrea T | authorlink2 = | last3 = Hughen | first3 = Ronald W | authorlink3 = | last4 = Light | first4 = Kathleen C | authorlink4 = Kathleen Light | title = Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects | journal = J Pain | volume = 10 | issue = 10 | pages = 1099-112 | date = Jul 31, 2009 | pmid = 19647494 | doi = 10.1016/j.jpain.2009.06.003 | url = http://www.jpain.org/article/S1526-5900(09)00574-4/abstract }}</ref><ref name="LightAR2011">{{citation | last1 = Light | first1 = Alan R | authorlink1 = Alan Light | last2 = Bateman | first2 = Lucinda| authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D | authorlink3 = Daehyun Jo | last4 = Hughen | first4 = Ronald W | authorlink4 = Ronald Hughen | last5 = Vanhaitsma | first5 = TA | authorlink5 = Timothy VanHaitsma | last6 = White | first6 = Andrea T | authorlink6 = Andrea White | last7 =Light | first7 = Kathleen C | authorlink7 = Kathleen Light | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome | journal = J Intern Med | volume = 271 | issue = 1 | pages = 64-81 | date = Jul 13, 2011 | pmid = 21615807 | doi = 10.1111/j.1365-2796.2011.02405.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02405.x/abstract }}</ref><ref name="WhiteAT2012">{{citation | last1 = White | first1 = Andrea T | authorlink1 = Andrea White | last2 = Light | first2 = Alan R | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W | authorlink3 = Ronald Hughen | last4 = VanHaitsma | first4 = Timothy A | authorlink4 = Timothy VanHaitsma | last5 = Light | first5 = Kathleen C | authorlink5 = Kathleen Light | title = Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls | journal = Psychosom Med | volume = 74 | issue = 1 | pages = 46-54 | date = Dec 30, 2011 | pmid = 22210239 | doi = 10.1097/PSY.0b013e31824152ed | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/ }}</ref>
* decreased [[oxygen]] utilization<ref>{{Cite journal | last = Vermeulen | first = Ruud CW | authorlink = Ruud Vermeulen | last2 = Vermeulen van Eck | first2 = Ineke WG| date = 2014 | title = Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome|url=https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-20|journal=Journal of Translational Medicine|language=en|volume=12|issue=1|pages=20|doi=10.1186/1479-5876-12-20|issn=1479-5876|pmc=3903040|pmid=24456560}}</ref>

[[File:Abnormal findings in CFS ME.png|thumb|center|alt=Abnormal findings in Chronic fatigue syndrome and myalgic encephalomyelitis. There is no single biomarker, but tests have found differences in blood flow to the brain, hand grip strength, metabolite and mitochondria abnormalities, reduced heart output, white and red blood cell differences, reduced blood volume, differences in gut bacteria, neuroinflammation, abnormal responses to exercise, and other abnormalities.]]

== See also ==
* [[Myalgic encephalomyelitis]]
* [[List of systematic reviews about ME/CFS]]
* [[:Category:Abnormal findings|Abnormal findings (images)]]

== Learn more ==
* [https://www.mdpi.com/2075-4418/9/2/41 Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (2019)] - original research article
* [http://www.meaction.net/wp-content/uploads/2015/05/ME2FCFS-RESEARCH-SUMMARY-Jamie-Seltzer.pdf #MEAction ME/CFS Research Summary]

==References==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Lists]]

SEPTAD

2023-12-06T18:46:22Z

JenB:Added pots

The SEPTAD is a name given by some clinicians treating [[Myalgic encephalomyelitis]] and [[Mast cell activation syndrome]] to a constellation of comorbidities and pathophysiological or pathogenic processes that tend to make up these patients’ clinical presentations.

The SEPTAD include:

* [[Ehlers-Danlos Syndrome]] / [[Hypermobility]]
* [[Dysautonomia]] and [[Postural orthostatic tachycardia syndrome]]
* [[Mast cell activation syndrome]]
* Chronic infections (for example, [[COVID-19]], [[Lyme disease|Lyme]], [[Coxsackie B virus|Coxsackie B4]], [[Epstein-Barr virus|Epstein-Barr Virus]])
* [[Gastroparesis]] and [[Small intestinal bacterial overgrowth|Small intestine bacterial overgrowth]]
* [[Autommunity]]
* Neurosurgical conditions (e.g., [[craniocervical instability]], [[atlantoaxial instability]], [[tethered cord syndrome]], [[Eagle’s syndrome]])
The name was originally coined by clinicians who are members of the MASTerminds listserv.

SEPTAD

2023-12-06T18:45:55Z

JenB:Added chronic infections

The SEPTAD is a name given by some clinicians treating [[Myalgic encephalomyelitis]] and [[Mast cell activation syndrome]] to a constellation of comorbidities and pathophysiological or pathogenic processes that tend to make up these patients’ clinical presentations.

The SEPTAD include:

* [[Ehlers-Danlos Syndrome]] / [[Hypermobility]]
* [[Dysautonomia]]
* [[Mast cell activation syndrome]]
* Chronic infections (for example, [[COVID-19]], [[Lyme disease|Lyme]], [[Coxsackie B virus|Coxsackie B4]], [[Epstein-Barr virus|Epstein-Barr Virus]])
* [[Gastroparesis]] and [[Small intestinal bacterial overgrowth|Small intestine bacterial overgrowth]]
* [[Autommunity]]
* Neurosurgical conditions (e.g., [[craniocervical instability]], [[atlantoaxial instability]], [[tethered cord syndrome]], [[Eagle’s syndrome]])
The name was originally coined by clinicians who are members of the MASTerminds listserv.

SEPTAD

2023-12-06T18:42:27Z

JenB:Added MASTerminds

The SEPTAD is a name given by some clinicians treating [[Myalgic encephalomyelitis]] and [[Mast cell activation syndrome]] to a constellation of comorbidities and pathophysiological or pathogenic processes that tend to make up these patients’ clinical presentations.

The SEPTAD include:

* [[Ehlers-Danlos Syndrome]] / [[Hypermobility]]
* [[Dysautonomia]]
* [[Mast cell activation syndrome]]
* Chronic infections
* [[Gastroparesis]] and [[Small intestinal bacterial overgrowth|Small intestine bacterial overgrowth]]
* [[Autommunity]]
* Neurosurgical conditions (e.g., [[craniocervical instability]], [[atlantoaxial instability]], [[tethered cord syndrome]], [[Eagle’s syndrome]])
The name was originally coined by clinicians who are members of the MASTerminds listserv.

SEPTAD

2023-12-06T18:41:57Z

JenB:Added components of SEPTAD

The SEPTAD is a name given by some clinicians treating [[Myalgic encephalomyelitis]] and [[Mast cell activation syndrome]] to a constellation of comorbidities and pathophysiological or pathogenic processes that tend to make up these patients’ clinical presentations.

The SEPTAD include:

* [[Ehlers-Danlos Syndrome]] / [[Hypermobility]]
* [[Dysautonomia]]
* [[Mast cell activation syndrome]]
* Chronic infections
* [[Gastroparesis]] and [[Small intestinal bacterial overgrowth|Small intestine bacterial overgrowth]]
* [[Autommunity]]
* Neurosurgical conditions (e.g., [[craniocervical instability]], [[atlantoaxial instability]], [[tethered cord syndrome]], [[Eagle’s syndrome]])

SEPTAD

2023-12-06T18:37:23Z

JenB:Created page

The SEPTAD is a name given by some clinicians treating [[Myalgic encephalomyelitis]] and [[Mast cell activation syndrome]].

Craniocervical instability

2023-08-15T21:47:29Z

JenB:

[[File:Craniocervical-instability-CCI.png|thumb|'''Craniocervical instability''' 
MRI of a patient's cervical spine, showing C1 and C2 radiation necrosis with C1-2 instability, cancer in the nasopharynx, and narrowing of the central canal at C1. 
Source: Choi, Y., Woo, S. W., & Lee, J.H. (2018). [https://www.anesth-pain-med.org/m/journal/view.php?id=10.17085/apm.2018.13.4.383 Awake fiberoptic orotracheal intubation using a modified Guedel airway in a patient with craniocervical instability and an anticipated difficult airway: A case report]. Anesthesia and Pain Medicine, 13(4), 383-387. Fig 1.<ref name="Choi2018">{{Cite journal | last = Choi|first = Yongjoon | last2 = Woo | first2 = Sung-won | last3 = Lee | first3 = Ji Heui | date = 2018-10-31 | title = Awake fiberoptic orotracheal intubation using a modified Guedel airway in a patient with craniocervical instability and an anticipated difficult airway - A case report - | url = https://www.anesth-pain-med.org/m/journal/view.php?id=10.17085/apm.2018.13.4.383|journal=Anesthesia and Pain Medicine|volume=13|issue=4 | pages = 383–387|doi=10.17085/apm.2018.13.4.383|issn=2383-7977}}</ref> License: CC BY-NC-4.0]]
'''Craniocervical instability''' (CCI) is a pathological condition of increased mobility at the craniocervical junction, the area where the skull meets the spine. In CCI the ligamentous connections of the craniocervical junction can be stretched, weakened or ruptured.<ref name=":2">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Austin | first2 = Claudiu | last3 = Benzel | first3 = Edward | last4 = Bolognese | first4 = Paolo | last5 = Ellenbogen | first5 = Richard | last6 = Francomano | first6 = Clair A. | last7 = Ireton | first7 = Candace | last8 = Klinge | first8 = Petra | last9 = Koby | first9 = Myles | date = 2017 | title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1 | pages = 195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref> This can lead to stretching and/or compression of the [[Brainstem compression|brainstem]], upper [[spinal cord]], or cerebellum and result in myelopathy, neck pain and a range of other symptoms.<ref name=":11">{{Cite journal | last = Choi|first = Sung Ho | last2 = Lee | first2 = Sang Gu | last3 = Park | first3 = Chan Woo | last4 = Kim | first4 = Woo Kyung | last5 = Yoo | first5 = Chan Jong | last6 = Son | first6 = Seong | date = Apr 2013 | title = Surgical Outcomes and Complications after Occipito-Cervical Fusion Using the Screw-Rod System in Craniocervical Instability | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698232/|journal=Journal of Korean Neurosurgical Society|volume=53|issue=4 | pages = 223–227|doi=10.3340/jkns.2013.53.4.223|issn=2005-3711|pmc=3698232|pmid=23826478}}</ref>

CCI can develop as a result of physical trauma such as a car accident, an inflammatory disease such as rheumatoid arthritis, a congenital disorder such as Down's syndrome<ref name=":10">{{Cite journal | last = Ashafai|first = Nabeel S. | last2 = Visocchi | first2 = Massimiliano | last3 = Wąsik | first3 = Norbert | date = 2019 | title=Occipitocervical Fusion: An Updated Review | url =https://www.ncbi.nlm.nih.gov/pubmed/30610329|journal=Acta Neurochirurgica. Supplement|volume=125 | pages = 247–252|doi=10.1007/978-3-319-62515-7_35|issn=0065-1419|pmid=30610329}}</ref>, or infection<ref name=":21" /><ref>{{Cite journal|title=Atlantoaxial Instability: Practice Essentials, Pathophysiology, Etiology|date=2023-07-17|url=https://emedicine.medscape.com/article/1265682-overview#a1}}</ref><ref name=":22" /><ref name=":23" />. More recently, physicians have reported an increased prevalence of CCI in patients with hereditary disorders of connective tissue such as Ehlers Danlos Syndromes (EDS).<ref name=":9">{{Cite journal | last = Henderson | first = Fraser C. | date = 2016 | title=Cranio-cervical Instability in Patients with Hypermobility Connective Disorders |url =https://www.omicsonline.org/open-access/craniocervical-instability-in-patients-with-hypermobility-connective-disorders-2165-7939-1000299.php?aid=71754|journal=Journal of Spine|language=en|volume=05|issue=02|doi=10.4172/2165-7939.1000299|issn=2165-7939}}</ref> There have also been anecdotal reports of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) who were later diagnosed with CCI (as well as [[tethered cord syndrome]]),<ref>{{Cite web | url = https://forums.phoenixrising.me/index.php?threads/have-you-ruled-out-chiari-as-a-cause-of-your-cfs.56908/ | title = Have you ruled out Chiari as a cause of your CFS | last = | first = | date = | website = Phoenix Rising| archive-url = | archive-date = |url-status = | access-date=}}</ref><ref>{{Cite web | url = https://medium.com/@jenbrea/cci-tethered-cord-series-e1e098b5edf | title = CCI + Tethered cord series | last = Brea | first = Jennifer | date = 2019-06-06 | website = Medium|language=en|access-date=2019-06-06}}</ref><ref>{{Cite web | url = https://www.mechanicalbasis.org/interviews.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-06}}</ref> although no scientific publication on this subject exists. It frequently co-occurs with [[atlantoaxial instability]] (AAI).{{Citation needed|reason= | date = 10 December 2019}}
== Symptoms ==
Symptoms of craniocervical instability include occipital [[headache]], [[neck pain]] and [[Nervous system|neurological]] abnormalities such as [[numbness]], [[paresis|motor weakness]], [[dizziness]], and [[gait instability]].<ref>{{Cite journal | last = Bobinski|first = Lukas | last2 = Levivier | first2 = Marc | last3 = Duff | first3 = John M. | date = Feb 2015 | title = Occipitoaxial spinal interarticular stabilization with vertebral artery preservation for atlantal lateral mass failure | url =https://www.ncbi.nlm.nih.gov/pubmed/25415481|journal=Journal of Neurosurgery Spine|volume=22|issue=2 | pages = 134–138|doi=10.3171/2014.10.SPINE14131|issn=1547-5646|pmid=25415481}}</ref><ref>{{Cite journal | last = O'Brien | first = Michael F. | last2 = Casey | first2 = Adrian T.H. | last3 = Crockard | first3 = Alan | last4 = Pringle | first4 = Jean | last5 = Stevens | first5 = John M. | date = 2002-10-15 | title = Histology of the craniocervical junction in chronic rheumatoid arthritis: a clinicopathologic analysis of 33 operative cases |url =https://www.ncbi.nlm.nih.gov/pubmed/12394902|journal=Spine|volume=27|issue=20 | pages = 2245–2254|doi=10.1097/01.BRS.0000029252.98053.43|issn=1528-1159|pmid=12394902}}</ref><ref>{{Cite journal | last = Young|first = Richard M. | last2 = Sherman | first2 = Jonathan H. | last3 = Wind | first3 = Joshua J. | last4 = Litvack | first4 = Zachary | last5 = O'Brien | first5 = Joseph | date = Aug 2014 | title = Treatment of craniocervical instability using a posterior-only approach: report of 3 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/24785968|journal=Journal of Neurosurgery. Spine|volume=21|issue=2 | pages = 239–248|doi=10.3171/2014.3.SPINE13684|issn=1547-5646|pmid=24785968}}</ref><ref>{{Cite journal | last = Botelho|first = Ricardo V. | last2 = Neto | first2 = Eliseu B. | last3 = Patriota | first3 = Gustavo C. | last4 = Daniel | first4 = Jefferson W. | last5 = Dumont | first5 = Paulo A.S. | last6 = Rotta | first6 = José M. | date = Oct 2007 | title = Basilar invagination: craniocervical instability treated with cervical traction and occipitocervical fixation. Case report | url = https://www.ncbi.nlm.nih.gov/pubmed/17933321|journal=Journal of Neurosurgery. Spine|volume=7|issue=4 | pages = 444–449|doi=10.3171/SPI-07/10/444|issn=1547-5654|pmid=17933321}}</ref><ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Henderson | first2 = Fraser C. | last3 = Wilson | first3 = William A. | last4 = Mark | first4 = Alexander S. | last5 = Koby | first5 = Myles | date = Jan 2018 | title = Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review | url =https://www.ncbi.nlm.nih.gov/pubmed/28258417|journal=Neurosurgical Review|volume=41|issue=1 | pages = 149–163|doi=10.1007/s10143-017-0830-3|issn=1437-2320|pmc=5748419|pmid=28258417|quote=|via=}}</ref> Patients sometimes describe the feeling that their head is too heavy for their neck to support (“bobble-head”).<ref name=":9" /> No particular symptom is mandatory for a diagnosis of CCI and each symptom listed might have a cause other than CCI.

Other symptoms reported in patients with CCI include:
* [[Muscle weakness]],<ref name=":0">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Francomano | first2 = C.A. | last3 = Koby | first3 = M. | last4 = Tuchman | first4 = K. | last5 = Adcock | first5 = J. | last6 = Patel | first6 = S. | date = 2019-01-09 | title = Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization | url =https://doi.org/10.1007/s10143-018-01070-4|journal=Neurosurgical Review|volume=92|issue= | pages = 915–936|language=en|doi=10.1007/s10143-018-01070-4|issn=1437-2320}}</ref> [[numbness|numbness,]]<ref name=":1">{{Cite journal | last = Francomano|first = Clair A. | last2 = McDonnell | first2 = Nazli B. | last3 = Nishikawa | first3 = Misao | last4 = Bolognese | first4 = Paolo A. | last5 = Milhorat | first5 = Thomas H. | date = 2007-12-01 | title = Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and Chiari malformation Type I in patients with hereditary disorders of connective tissue | url =https://thejns.org/view/journals/j-neurosurg-spine/7/6/article-p601.xml|journal=Journal of Neurosurgery: Spine|language=en-US|volume=7|issue=6 | pages = 601–609|doi=10.3171/SPI-07/12/601}}</ref><ref name=":2" /> [[paralysis]], [[paresthesia]]s<ref name=":0" /><ref name=":4">{{Cite web | url = https://search.proquest.com/openview/34b3b18a8854c04ffa0fc50273d68313/1?pq-origsite=gscholar&cbl=47886 | title = MRI video diagnosis and surgical therapy of soft tissue trauma to the craniocervical junction - ProQuest | website = search.proquest.com|language=en|access-date=2019-06-01}}</ref><ref name=":5">{{Cite journal | last = Rebbeck|first = Trudy | last2 = Liebert | first2 = Ann | date = 2014-12-01 | title = Clinical management of cranio-vertebral instability after whiplash, when guidelines should be adapted: A case report | url = http://www.sciencedirect.com/science/article/pii/S1356689X14000101|journal=Manual Therapy|volume=19|issue=6 | pages = 618–621|doi=10.1016/j.math.2014.01.009|issn=1356-689X}}</ref><ref name=":6">{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult Hypermobility of the Craniocervical Junction: A Case Report and Review | url =https://www.jospt.org/doi/full/10.2519/jospt.2011.3305|journal=Journal of Orthopaedic & Sports Physical Therapy|language=en|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=0190-6011}}</ref>
* Poor [[proprioception]],<ref name=":7">{{Cite journal | last = Bergholm|first = Ulla | last2 = Johansson | first2 = Bengt H. | last3 = Johansson | first3 = Hakan | date = 2004-01-01 | title = New Diagnostic Tools Can Contribute to Better Treatment of Patients with Chronic Whiplash Disorders |url =https://doi.org/10.3109/J180v03n02_02|journal=Journal of Whiplash & Related Disorders|volume=3|issue=2 | pages = 5–19|doi=10.3109/J180v03n02_02|issn=1533-2888}}</ref> [[impaired coordination]], [[gait]] changes<ref name=":0" /><ref name=":7" />
* [[Dizziness]], [[vertigo|vertigo,]]<ref name=":0" /><ref name=":2" /><ref name=":7" /><ref name=":4" /><ref name=":6" /><ref name=":5" /> syncope,<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":7" /> nausea<ref name=":1" /><ref name=":2" />
* [[Tension-type headache|Headache behind the eyes]],<ref name=":6" /> [[stiff neck|neck stiffness]], torticollis,<ref name=":7" /><ref>{{Cite journal | last = Ghanem|first = Ismat | last2 = El Hage | first2 = Samer | last3 = Rachkidi | first3 = Rami | last4 = Kharrat | first4 = Khalil | last5 = Dagher | first5 = Fernand | last6 = Kreichati | first6 = Gabi | date = 2008-03-01 | title = Pediatric cervical spine instability | url = https://online.boneandjoint.org.uk/doi/full/10.1007/s11832-008-0092-2|journal=Journal of Children's Orthopaedics|volume=2|issue=2 | pages = 71–84|doi=10.1007/s11832-008-0092-2|issn=1863-2521|pmc=2656787|pmid=19308585}}</ref> posterior scalp irritation,<ref name=":7" /> [[facial pain]]
* Apnea,<ref>{{Cite journal | last = Janjua | first = M. Burhan | last2 = Hwang | first2 = Steven W. | last3 = Samdani | first3 = Amer F. | last4 = Pahys | first4 = Joshua M. | last5 = Baaj | first5 = Ali A. | last6 = Härtl | first6 = Roger | last7 = Greenfield | first7 = Jeffrey P. | date = 2019-01-01 | title = Instrumented arthrodesis for non-traumatic craniocervical instability in very young children | url =https://doi.org/10.1007/s00381-018-3876-9|journal=Child's Nervous System|language=en|volume=35|issue=1 | pages = 97–106|doi=10.1007/s00381-018-3876-9|issn=1433-0350}}</ref><ref name=":1" /><ref name=":3">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Austin | first2 = Claudiu | last3 = Benzel | first3 = Edward | last4 = Bolognese | first4 = Paolo | last5 = Ellenbogen | first5 = Richard | last6 = Francomano | first6 = Clair A. | last7 = Ireton | first7 = Candace | last8 = Klinge | first8 = Petra | last9 = Koby | first9 = Myles | date = 2017 | title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1 | pages = 195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref> [[dyspnea]] (shortness of breath),<ref name=":0" /><ref name=":1" /> and [[dysphagia]] (difficulty swallowing)<ref name=":1" /><ref name=":2" />
* [[visual dysfunction|Visual disturbance]]s<ref name=":4" /> downward [[nystagmus]] (irregular eye movements),<ref name=":1" /><ref name=":7" /> [[tinnitus]]<ref>{{Cite journal | last = Montazem|first = Abbas | authorlink = | date = 2000 | title = Secondary tinnitus as a symptom of instability in the upper cervical spine: Operative management | url = https://www.tinnitusjournal.com/articles/secondary-tinnitus-as-a-symptom-ofinstability-of-the-upper-cervical-spineoperative-management.pdf | journal=International Tinnitus Journal|volume=6|issue=2 | pages = 130-3|pmid=14689631|quote=|via=}}</ref><ref name=":4" />
* [[Fatigue]],<ref name=":0" /><ref name=":14">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Henderson | first2 = Fraser C. | last3 = Wilson | first3 = William A. | last4 = Mark | first4 = Alexander S. | last5 = Koby | first5 = Myles | date = 2018-01-01 | title = Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review | url =https://doi.org/10.1007/s10143-017-0830-3|journal=Neurosurgical Review|language=en|volume=41|issue=1 | pages = 149–163|doi=10.1007/s10143-017-0830-3|issn=1437-2320|pmc=5748419|pmid=28258417}}</ref><ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Wilson | first2 = William A. | last3 = Mott | first3 = Stephen | last4 = Mark | first4 = Alexander | last5 = Schmidt | first5 = Kristi | last6 = Berry | first6 = Joel K. | last7 = Vaccaro | first7 = Alexander | last8 = Benzel | first8 = Edward | date = 2010-07-16 | title = Deformative stress associated with an abnormal clivo-axial angle: A finite element analysis |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940090/|journal=Surgical Neurology International|volume=1|doi=10.4103/2152-7806.66461|issn=2152-7806|pmc=2940090|pmid=20847911}}</ref> [[Sleep dysfunction]],<ref name=":0" /><ref name=":4" /> [[Cognitive dysfunction|cognitive impairment]],<ref name=":4" /> and [[Memory problems|memory loss]].

== Risk factors and comorbidities ==
Established risk factors for CCI include physical [[trauma]], infection, [[inflammation|inflammatory]] disease, neoplasms and congenital disorders.<ref name=":10" /><ref name=":12">{{Cite journal | last = Sapkas | first = George | last2 = Papadakis | first2 = Stamatios A | last3 = Segkos | first3 = Dimitrios | last4 = Kateros | first4 = Konstantinos | last5 = Tsakotos | first5 = George | last6 = Katonis | first6 = Pavlos | date = 2011-06-02 | title = Posterior Instrumentation for Occipitocervical Fusion | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139273/|journal=The Open Orthopaedics Journal|volume=5 | pages = 209–218|doi=10.2174/1874325001105010209|issn=1874-3250|pmc=3139273|pmid=21772931}}</ref>

More recently, physicians have reported an increased prevalence of CCI in patients with hereditary [[connective tissue disorder]]s.<ref name=":9" /> According to Brodbelt & Flint, however, an "increased range of joint movement, caused by ligamentous laxity, is not the same as [[spinal instability]] resulting from trauma or major inflammatory arthropathies such as (historically) [[rheumatoid arthritis]]."<ref name=":19">{{Cite journal | last = Brodbelt | first = Andrew R. | last2 = Flint | first2 = Graham | date = Aug 2017 | title = Ehlers Danlos, complex Chiari and cranio-cervical fixation: how best should we treat patients with hypermobility? | url = https://www.ncbi.nlm.nih.gov/pubmed/28961036|journal=British Journal of Neurosurgery|volume=31|issue=4 | pages = 397–398|doi=10.1080/02688697.2017.1386282|issn=1360-046X|pmid=28961036|pmc=|quote=|via=}}</ref> Others have argued that "pathological instability at the cranio-cervical junction has not been clearly established in the literature for the [[joint hypermobility]] population."<ref name=":9" />

{| class="wikitable"
|'''Cause of instability'''
|'''Example'''
|-
|Physical trauma<ref>{{Cite journal | last = Ghatan | first = Saadi | last2 = Newell | first2 = David W. | last3 = Grady | first3 = M. Sean | last4 = Mirza | first4 = Sohail K. | last5 = Chapman | first5 = Jens R. | last6 = Mann | first6 = Frederick A. | last7 = Ellenbogen | first7 = Richard G. | date = Aug 2004 | title = Severe posttraumatic craniocervical instability in the very young patient. Report of three cases |url =https://www.ncbi.nlm.nih.gov/pubmed/16206980|journal=Journal of Neurosurgery|volume=101|issue=1 Suppl | pages = 102–107|doi=10.3171/ped.2004.101.2.0102|issn=0022-3085|pmid=16206980}}</ref>
|Car accident<ref>{{Cite journal | last = Uribe | first = Juan S. | last2 = Ramos | first2 = Edwin | last3 = Baaj | first3 = Ali | last4 = Youssef | first4 = A. Samy | last5 = Vale | first5 = Fernando L. | date = Dec 2009 | title = Occipital cervical stabilization using occipital condyles for cranial fixation: technical case report | url = https://www.ncbi.nlm.nih.gov/pubmed/19934947|journal=Neurosurgery|volume=65|issue=6| pages = E1216–1217; discussion E1217|doi=10.1227/01.NEU.0000349207.98394.FA|issn=1524-4040|pmid=19934947}}</ref><ref>{{Cite journal | last = Volle | first = E. | last2 = Montazem | first2 = A. | date = Jan 2001 | title = MRI video diagnosis and surgical therapy of soft tissue trauma to the craniocervical junction | url =https://www.ncbi.nlm.nih.gov/pubmed/11209518|journal=Ear, Nose, & Throat Journal|volume=80|issue=1 | pages = 41–44, 46–48|issn=0145-5613|pmid=11209518}}</ref>, blow to the head.<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref>
|-
|Infection & inflammatory disease
|Upper respiratory infection<ref name=":21">{{Cite journal | last = Hettiaratchy|first = Shehan | last2 = Ning | first2 = Chou | last3 = Sabin | first3 = Ian | date = 1998-07-01 | title = Nontraumatic Atlanto-occipital and Atlantoaxial Rotatory Subluxation: Case Report | url = https://academic.oup.com/neurosurgery/article/43/1/162/2856810|journal=Neurosurgery|language=en|volume=43|issue=1 | pages = 162–164|doi=10.1097/00006123-199807000-00110|issn=0148-396X}}</ref><ref name=":22">{{Cite journal | last = Washington | first = Eleby R. | date = Mar 1959 | title = Non-Traumatic Atlanto-Occipital and Atlanto-Axial Dislocation: A Case Report | url = https://journals.lww.com/jbjsjournal/Citation/1959/41020/Non_Traumatic_Atlanto_Occipital_and_Atlanto_Axial.15.aspx|journal=JBJS|language=en-US|volume=41|issue=2 | pages = 341–344|issn=0021-9355}}</ref>, Rheumatoid arthritis<ref>{{Cite journal | last = O'Brien | first = Michael F. | last2 = Casey | first2 = Adrian T.H. | last3 = Crockard | first3 = Alan | last4 = Pringle | first4 = Jean | last5 = Stevens | first5 = John M. | date = 2002-10-15 | title = Histology of the craniocervical junction in chronic rheumatoid arthritis: a clinicopathologic analysis of 33 operative cases |url =https://www.ncbi.nlm.nih.gov/pubmed/12394902|journal=Spine|volume=27|issue=20 | pages = 2245–2254|doi=10.1097/01.BRS.0000029252.98053.43|issn=1528-1159|pmid=12394902}}</ref>, tuberculosis<ref name=":23">{{Cite journal | last = Chaudhary|first = Kshitij | last2 = Potdar | first2 = Prabodhan | last3 = Bapat | first3 = Mihir | last4 = Rathod | first4 = Ashok | last5 = Laheri | first5 = Vinod | date = 2012-06-15 | title = Structural odontoid lesions in craniovertebral tuberculosis: a review of 15 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/22261632|journal=Spine|volume=37|issue=14| pages = E836–843|doi=10.1097/BRS.0b013e31824a4c8f|issn=1528-1159|pmid=22261632}}</ref>
|-
|Neoplasms
|Tumors<ref name=":12" /> such as haemangioma, aneurysmal bone cyst
|-
|Congenital
|Down’s syndrome<ref>{{Cite journal | last = Hankinson | first = Todd C. | last2 = Anderson | first2 = Richard C.E. | date = Mar 2010 | title = Craniovertebral junction abnormalities in Down syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/20173525|journal=Neurosurgery|volume=66|issue=3 Suppl | pages = 32–38|doi=10.1227/01.NEU.0000365803.22786.F0|issn=1524-4040|pmid=20173525}}</ref>, os odontoideum<ref>{{Cite journal | last = Zhao|first = Deng | last2 = Wang | first2 = Shenglin | last3 = Passias | first3 = Peter G. | last4 = Wang | first4 = Chao | date = May 2015 | title = Craniocervical instability in the setting of os odontoideum: assessment of cause, presentation, and surgical outcomes in a series of 279 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/25635883|journal=Neurosurgery|volume=76|issue=5 | pages = 514–521|doi=10.1227/NEU.0000000000000668|issn=1524-4040|pmid=25635883}}</ref>, dwarfism
|-
|Hereditary connective tissue disorder
|Ehlers Danlos Syndromes<ref name=":0" /><ref name=":1" />
|-
|Fluoroquinolones
|Connective tissue weakening<ref name=":20">{{Cite journal | last = Etminan | first = M. | authorlink = | last2 = Sodhi | first2 = M. | authorlink2 = | last3 = Ganjizadeh-Zavareh | first3 = S. | author-link3 = | last4 = Carleton | first4 = B. | author-link4 = | last5 = Kezouh | first5 = A. | author-link5 = | last6 = Brophy | first6 = J.M. | author-link6 = | date = 2019-09-17 | title = Oral Fluoroquinolones and Risk of Mitral and Aortic Regurgitation | url =https://www.sciencedirect.com/science/article/pii/S0735109719359789|journal=Journal of the American College of Cardiology|language=en|volume=74|issue=11 | pages = 1444–1450|doi=10.1016/j.jacc.2019.07.035|issn=0735-1097|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref>{{Cite journal | last = Demetrious | first = James S. | date = 2018-07-09 | title = Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? | url = https://doi.org/10.1186/s12998-018-0193-z|journal=Chiropractic & Manual Therapies|volume=26|issue=1 | pages = 22|doi=10.1186/s12998-018-0193-z|issn=2045-709X}}</ref>, tendon ruptures<ref>{{Cite journal | last = Stephenson | first = Anne L. | last2 = Wu | first2 = Wei | last3 = Cortes | first3 = Daniel | last4 = Rochon | first4 = Paula A. | date = Sep 2013 | title = Tendon Injury and Fluoroquinolone Use: A Systematic Review | url =https://pubmed.ncbi.nlm.nih.gov/23888427/#|journal=Drug Safety|volume=36|issue=9 | pages = 709–721|doi=10.1007/s40264-013-0089-8|issn=1179-1942|pmid=23888427}}</ref>
|}
It is not unusual for CCI to co-occur with other structural neurological abnormalities such as [[atlantoaxial instability]] (AAI) and [[chiari malformation]] (CM).<ref>{{Cite journal | last = Camino Willhuber | first = Gaston O. | last2 = Bosio | first2 = Santiago T. | last3 = Puigdevall | first3 = Miguel H. | last4 = Halliburton | first4 = Carolina | last5 = Sola | first5 = Carlos A. | last6 = Maenza | first6 = Ruben A. | date = Jan 2017 | title = Craniocervical spinal instability after type 1 Arnold Chiari decompression: a case report | url = https://www.ncbi.nlm.nih.gov/pubmed/27258364|journal=Journal of Pediatric Orthopedics. Part B|volume=26|issue=1 | pages = 80–85|doi=10.1097/BPB.0000000000000346|issn=1473-5865|pmid=27258364}}</ref><ref name=":0" />

== Diagnosis ==
{{Video|id=https://youtu.be/MsYDA3SXTkg|service=youtube|dimensions=550|description=Dr. Paolo Bolognese discusses methods of imaging and measurement for diagnosis.|alignment=right|urlargs=}}
The diagnosis of CCI is based on symptom presentation, a supportive history, demonstrable neurological findings and abnormal imaging.

=== Imaging ===
CCI is typically diagnosed via a cervical [[Magnetic resonance imaging|MRI]], whether supine or upright. If supine, a 3 Tesla MRI is preferred over a 1.5 Tesla. Most neurosurgeons prefer upright MRI with flexion and extension.{{citation needed | date = 2021 | reason=source not meeting scientific guidelines}}<ref>{{Cite web | url = https://www.mechanicalbasis.org/diagnosis.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-02}}</ref> According to Henderson FC, “ventral [[brainstem]] compression may exist in flexion of the cervical spine, but appear normal on routine imaging.”<ref name=":9" />

{| class="wikitable"
!Imaging
!Sensitive for
|-
|Upright MRI with flexion/extension
|Horizontal instability
|-
|CT scan with rotation
|Rotational instability
|-
|Invasive cervical traction (ICT) with fluoroscopy
|Vertical instability
|}

=== Measurements ===
More than twenty radiological measurements have been proposed or used in the diagnosis of CCI. However, three measurements are most commonly used: the [[Grabb-Oakes measurement|Grabb-Oakes]] line, which measures ventral brainstem compression; the [[Clivo-axial angle|Clivo-Axial Angle (CXA)]], which measures brainstem deformity by the [[odontoid]] process; and the Basion Dens Interval, which measures vertical instability ([[cranial settling]]). According to a 2013 consensus statement on the assessment of CCI, a CXA of 135 degrees or less should be considered as "potentially pathological."<ref name=":13">{{Cite web | url = https://bobbyjonescsf.org/csf-video/review-colloq-2014/ | title = REVIEW OF THE 2013 CSF RESEARCH COLLOQUIUM & CONSENSUS ON CRANIOCERVICAL INSTABILITY – Bobby Jones CSF | last = CSF|first = Bobby Jones {{!}}|language=en-US|access-date=2019-09-18}}</ref> as it is reported to be uncommon in the healthy population.<ref>{{Cite journal | last = Batista | first = Ulysses C. | last2 = Joaquim | first2 = Andrei F. | last3 = Fernandes | first3 = Yvens B. | last4 = Mathias | first4 = Roger N. | last5 = Ghizoni | first5 = Enrico | last6 = Tedeschi | first6 = Helder | date = Apr 2015 | title = Computed tomography evaluation of the normal craniocervical junction craniometry in 100 asymptomatic patients |url =https://www.ncbi.nlm.nih.gov/pubmed/25828499|journal=Neurosurgical Focus|volume=38|issue=4| pages = E5|doi=10.3171/2015.1.FOCUS14642|issn=1092-0684|pmid=25828499}}</ref><ref>{{Cite journal | last = Botelho|first = Ricardo Vieira | last2 = Ferreira | first2 = Edson Dener Zandonadi | date = Oct 2013 | title = Angular craniometry in craniocervical junction malformation | url =https://www.ncbi.nlm.nih.gov/pubmed/23640096|journal=Neurosurgical Review|volume=36|issue=4 | pages = 603–610; discussion 610|doi=10.1007/s10143-013-0471-0|issn=1437-2320|pmc=3910287|pmid=23640096}}</ref><ref>{{Cite journal | last = Bundschuh|first = C | last2 = Modic | first2 = Mt | last3 = Kearney | first3 = F | last4 = Morris | first4 = R | last5 = Deal | first5 = C | date = 1988-07-01 | title = Rheumatoid arthritis of the cervical spine: surface-coil MR imaging | url =https://www.ajronline.org/doi/abs/10.2214/ajr.151.1.181|journal=American Journal of Roentgenology|volume=151|issue=1 | pages = 181–187|doi=10.2214/ajr.151.1.181|issn=0361-803X}}</ref> Others have argued that these radiological measurements are "not accepted internationally as indicating instability."<ref name=":19" />
{| class="wikitable"
|+
!Measurement
!Units
!Description
! scope="col" style="width: 75px;" | Normal Range
! scope="col" style="width: 75px;" | Borderline Range
! scope="col" style="width: 75px;" | Pathological Range
! scope="col" style="width: 75px;" | Alternate Ranges
!Instability Measured
!Pathology Measured
!Refs
|-
|'''Clivo-axial angle (CXA)'''
|Degrees
|Angle between clivus line and the posterior axial line
|170 -150
|149 -136
|≤ 135
|
|More sensitive for horizontal
|Brainstem deformity
|<ref name="Bolognese2014yt">{{Cite web | last = Bolognese | first = Paolo | authorlink = | date = 2014 | title = Videoed Presentation at: ASAP Chiari & Syringomyelia Conference Paolo Bolognese, MD "Complex Chiari. Timecode 14:28 | url = https://www.youtube.com/watch?v=uiyk0Qbx2TQ&t=14m28s | website = YouTube|quote=|via=}}</ref>
|-
|'''Grabb-Oakes'''
|mm
|Distance from the dura to the line drawn from the basion to the posterior inferior edge of the C2 vertebra
|< 6
|≥ 6 and < 9
|≥ 9
|Some use pathological ≥ 8
|More sensitive for horizontal
|Brainstem compression
|<ref>{{Cite web | last = Bolognese | first = Paolo | authorlink = | date = April 12, 2018 | title = Videoed presentation at: EDS Awareness Educational Series. Timecodes: 49:30 and 53:47 | url = https://www.youtube.com/watch?v=MsYDA3SXTkg&t=49m30s | website = YouTube|quote=|via=}}</ref><ref name=":9" />
|-
|'''Basion-Axial Interval (BAI)'''
|mm
|Distance from tip of basion to posterior axial line
|< 12
|
|≥ 12
|
|
|
|<ref name=":15">{{Cite web | last = Henderson | first = Fraser | authorlink = | date = | title = Videoed presentation at: Chiari & Syringomyelia Foundation, Patient Conference of Action, June 24, 2018. Timecode: 10:34. | url = https://www.youtube.com/watch?list=WL&v=sEi9AlHQTJc&t=10m34s|journal=|volume=|issue=| pages=|quote=|via=}}</ref>
|-
|'''Basion-Dens interval (BDI)'''
|mm
|Vertical distance between the basion and the dens
|< 12
|
|≥ 12
|Some use pathological ≥ 10
|Vertical
|Cranial settling
|<ref name=":15" /><ref name=":9" />
|-
|'''Translational BAI'''
|mm
|Change in BAI between flexion and extension positions of the head
|< 1
|≥ 1 and ≤ 2
|> 2
|For surgery > 4 needed
|Horizontal
|Skull sliding over spine
|<ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Francomano | first2 = C.A. | last3 = Koby | first3 = M. | last4 = Tuchman | first4 = K. | last5 = Adcock | first5 = J. | last6 = Patel | first6 = S. | date = 2019-01-09 | title = Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization | url =https://doi.org/10.1007/s10143-018-01070-4|journal=Neurosurgical Review|language=en|doi=10.1007/s10143-018-01070-4|issn=1437-2320}}</ref><ref name=":0" />
|-
|'''Translational BDI'''
|mm
|Change in BDI between flexion and extension positions of the head
|
|
|
|
|
|
|
|-
|'''Dynamic BDI'''
|mm
|Change in BDI value when the head is pulled upward with traction force of typically up to 35 lbs
|
|
|
|
|Vertical
|Cranial settling
|
|-
|'''Dens Over Chamberlain'''
|mm
|How far tip of the dens extends above Chamberlain's line
|< 2
|≥ 2 and ≤ 3
|≥ 3
|
|Vertical
|Basilar invagination
|<ref>{{Cite web | last = Hain | first = Timothy C. | authorlink = | date = | title = Basilar Invagination, Basilar Impression and Atlantoaxial Subluxation | url =https://www.dizziness-and-balance.com/disorders/central/cerebellar/basilar%20invagination.htm | website = dizziness-and-balance.com|quote=|via=}}</ref>{{citation needed | date = 2022))
|}
Some of the measurement ranges in the above table are also to be found in the 2nd International CSF Dynamics Symposium Consensus Statement (2013).<ref name=":13" />

=== Traction ===
Manual traction, halo and invasive cervical traction may be used to aid in the diagnosis of CCI. Symptomatic improvement with traction can help determine whether a patient with abnormal measurements will benefit from craniocervical fusion surgery.

== Treatment ==
{{Video|id=https://youtu.be/sEi9AlHQTJc|service=youtube|dimensions=550|description=Dr. Fraser Henderson presents the results a five-year follow-up study.|alignment=right|urlargs=}}
=== Conservative treatment ===
Traditional “conservative” treatments for CCI include rest, pain management, upper cervical chiropractic treatment, and bracing with a cervical collar.<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref> Although, in most cases these offer little relief.

Other experimental treatments for CCI include prolotherapy and stem cell therapy.

=== Surgery ===
If non-invasive treatments for CCI fail to work, occipito-cervical fusion (OCF) can be considered.<ref name=":0" /> OCF is a surgery that aims at a biomechanical stabilization of the craniocervical junction. Patients with objective radiological findings, a clinical picture supportive of the diagnosis, a positive response to traction, and who are significantly impaired may be candidates for this surgery. A common method involves internal fixation of the upper spine to the skull by mechanical rods and screws. (However, rod-wire, rigid rod-screws, occipital hooks and cervical claws are all methods currently in use.<ref name=":16">{{Cite journal | last = Resnick|first = Daniel K. | last2 = Patel | first2 = Nirav J. | last3 = Lall | first3 = Rishi | date = 2010-11-01 | title = A Review of Complications Associated With Craniocervical Fusion Surgery | url = https://academic.oup.com/neurosurgery/article/67/5/1396/2563905|journal=Neurosurgery|language=en|volume=67|issue=5 | pages = 1396–1403|doi=10.1227/NEU.0b013e3181f1ec73|issn=0148-396X}}</ref>) During surgery, titanium hardware is used to fixate the occiput, axis and atlas (i.e., C0 to C2) while rib graft, cadaver bone graft or synthetic bone is used to help the bones fuse together. Wire methods are less biomechanically stable than rod methods and have high rates of dural laceration.<ref name=":16" /> Screw and rod fixation methods have lower complication rates and higher rates of successful fusion.<ref name=":18" /> Fusion rates across all hardware methods range from 89 to 100%.<ref name=":16" /> When cervical instability is present below C2, additional vertebrae may also be fused.

==== Outcomes, risks & complications ====
Little research on outcomes exists. In a small case study of 20 patients, the five-year outcome of OCF was generally favorable with most patients experiencing symptom relief post-surgery.<ref name=":0" /> In this study, following 20 EDS patients five years free O-2 fusion, most reported they were satisfied with the surgery and experienced significant improvements in symptoms such as vertigo, headaches, imbalance, dysarthria, dizziness, and frequent daytime urination. There was, however, only a small increase in objective outcomes such as work resumption, with 60% of patients remaining unable to work or go to school. Participants attributed this to other EDS comorbidities such as POTS, Mast Cell Activation Syndrome, and additional spinal problems.<ref name=":0" />

The complications of OCF can be serious<ref>{{Cite journal | last = Garrido|first = Ben J. | last2 = Sasso | first2 = Rick C. | date = Jan 2012 | title = Occipitocervical fusion | url =https://www.ncbi.nlm.nih.gov/pubmed/22082624|journal=The Orthopedic Clinics of North America|volume=43|issue=1 | pages = 1–9, vii|doi=10.1016/j.ocl.2011.08.009|issn=1558-1373|pmid=22082624}}</ref> and occur in an estimated 7% to 33% of patients.<ref name=":10" /><ref name=":18">{{Cite journal | last = Winegar | first = Corbett D. | last2 = Lawrence | first2 = James P. | last3 = Friel | first3 = Brian C. | last4 = Fernandez | first4 = Carmella | last5 = Hong | first5 = Joseph | last6 = Maltenfort | first6 = Mitchell | last7 = Anderson | first7 = Paul A. | last8 = Vaccaro | first8 = Alexander R. | date = Jul 2010 | title = A systematic review of occipital cervical fusion: techniques and outcomes |url =https://www.ncbi.nlm.nih.gov/pubmed/20594011|journal=Journal of Neurosurgery. Spine|volume=13|issue=1 | pages = 5–16|doi=10.3171/2010.3.SPINE08143|issn=1547-5646|pmid=20594011}}</ref><ref name=":11" /><ref>{{Cite journal | last = Ando|first = Kei | last2 = Imagama | first2 = Shiro | last3 = Ito | first3 = Zenya | last4 = Kobayashi | first4 = Kazuyoshi | last5 = Yagi | first5 = Hideki | last6 = Shinjo | first6 = Ryuichi | last7 = Hida | first7 = Tetsuro | last8 = Ito | first8 = Kenyu | last9 = Ishikawa | first9 = Yoshimoto | date = Jun 2017 | title = Minimum 5-year Follow-up Results for Occipitocervical Fusion Using the Screw-Rod System in Craniocervical Instability | url = https://www.ncbi.nlm.nih.gov/pubmed/28525489|journal=Clinical Spine Surgery|volume=30|issue=5| pages = E628–E632|doi=10.1097/BSD.0000000000000199|issn=2380-0194|pmid=28525489}}</ref><ref name=":16" /> Common complications include screw failure, wound infection, dural tear and cerebrospinal fluid leakage<ref name=":11" /> In some cases revision surgery is needed to treat infection or to remove hardware. Severe complications can include meningitis and accidental injury of the vertebral artery by misplaced screws.<ref name=":17">{{Cite journal | last = Nockels | first = Russ P. | last2 = Shaffrey | first2 = Christopher I. | last3 = Kanter | first3 = Adam S. | last4 = Azeem | first4 = Syed | last5 = York | first5 = Julie E. | date = Aug 2007 | title = Occipitocervical fusion with rigid internal fixation: long-term follow-up data in 69 patients |url =https://www.ncbi.nlm.nih.gov/pubmed/17688049|journal=Journal of Neurosurgery. Spine|volume=7|issue=2 | pages = 117–123|doi=10.3171/SPI-07/08/117|issn=1547-5654|pmid=17688049}}</ref>

A meta-study of 2274 procedures across 22 studies<ref name=":16" /> found the following complication rates:

{| class="wikitable"
!Complication type
!Prevalence rate
|-
|Hardware failure after fusion non-union
|7%
|-
|Wound infection
|3.8%-11%
|-
|Vertebral artery damage
|1.3%-4.1%
|-
|Dural tears
|0% to 4.2%
|}
Meta-studies place the rate of death from fusion surgery at 0-0.6%.<ref name=":16" /><ref name=":18" />

==== Side effects ====
OCF causes a substantial reduction in the neck’s range of motion, estimated at approximately 40% of total cervical flexion–extension.<ref name=":8">{{Cite book | last = Ashafai|first = Nabeel S. | last2 = Visocchi | first2 = Massimiliano | last3 = Wąsik | first3 = Norbert | date = 2019 | editor-last = Visocchi|editor-first = Massimiliano | title = Occipitocervical Fusion: An Updated Review | url =https://doi.org/10.1007/978-3-319-62515-7_35|series=Acta Neurochirurgica Supplement|language=en|location=Cham| publisher = Springer International Publishing | pages = 247–252|doi=10.1007/978-3-319-62515-7_35|isbn=9783319625157}}</ref>

==== Cost ====
OCF is estimated to cost tens of thousands of dollars, although some insurance schemes fully cover the cost of surgery depending on the country located and neurosurgeons involved.

=== Experimental treatments ===
* '''[[Stem cell therapy]]:''' Some clinics offer stem cell therapy in order to regenerate the area, ligaments, connective and other tissues that may be damaged in the area, e.g. Centeno-Schultz Clinic.<ref>https://centenoschultz.com/cervical-joint-degeneration/</ref>

*'''[[Platelet-rich plasma therapy|Platelet-Rich Plasma therapy]] (PRP therapy)''': Some clinics offer PRP therapy in order to help the body regenerate the area, e.g. Regenexx clinic.<ref>https://regenexx.com/blog/candidacy-for-ccj-instability-procedure/</ref><ref>https://www.nwrestorativemedicine.com/pain-solutions/neck-pain/</ref>

*'''[[Percutaneous implantation of the CCJ ligaments]]''' (PICL): A non-surgical treatment involving injecting your own bone marrow concentrate to strengthen ligaments.<ref name="picl">https://centenoschultz.com/craniocervical-instability-cci/</ref>

== Dysautonomia and CCI in EDS ==
As CCI can lead to a compression of the brainstem, a number of experts believe it contributes to autonomic symptoms such as orthostatic tachycardia, dizziness and pre-/syncope that are frequently seen in patients with Ehlers Danlos Syndromes (EDS). In a 2007 influential paper Milhorat et al. followed-up on patients with Chiari malformation who did not improve with treatment and surgery. The authors discovered that many of these patients suffered from EDS and had other structural abnormalities at the upper spine such as CCI and cranial settling. Milhorat et al. speculated that the resulting compression of the brainstem might be the cause of the autonomic and other symptoms these patients were suffering from.<ref>{{Cite journal | last = Milhorat | first = Thomas H. | last2 = Bolognese | first2 = Paolo A. | last3 = Nishikawa | first3 = Misao | last4 = McDonnell | first4 = Nazli B. | last5 = Francomano | first5 = Clair A. | date = Dec 2007 | title = Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue | url =https://www.ncbi.nlm.nih.gov/pubmed/18074684|journal=Journal of Neurosurgery. Spine|volume=7|issue=6 | pages = 601–609|doi=10.3171/SPI-07/12/601|issn=1547-5654|pmid=18074684}}</ref> Neurosurgeons and other EDS specialists have expounded on the connection between CCI and forms of dysautonomia such as postural orthostatic tachycardia syndrome (POTS) in a number of conference presentations. <ref>[https://www.youtube.com/watch?time_continue=735&v=857Jsjsqxjw Craniocervical Instability (Dr Henderson the 2012 EDNF Confrence).] Minute 12.10. </ref><ref>[https://www.youtube.com/watch?v=ntD9NRIvEJ0 Dr Milhorat from The Chiari Institute at the 2005 ASAP.]</ref><ref name=":13" />

== Mechanical basis theory ==
Dozens of ME/CFS patients diagnosed with CCI (some also had EDS) reported to have experienced remarkable improvements and even remission of their ME/CFS symptoms following OCF-surgery.<ref>{{Cite web | url = https://www.mechanicalbasis.org/interviews.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-06}}</ref><ref>{{Cite web | url = https://medium.com/@jenbrea/health-update-3-my-me-is-in-remission-dd575e650f71 | title = Health update #3: My ME is in remission | last = Brea | first = Jennifer | date = 2019-05-20 | website = Medium|access-date=2019-06-03}}</ref> They speculate that mechanical compression of the brainstem due to CCI, or other underlying structural conditions, have the potential to cause characteristic ME/CFS symptoms such as post-exertional malaise, although there have not been any studies regarding this particular theory.
Some have raised concerns about CCI surgery in patients with ME/CFS given the lack of research on OCF in this patient population.<ref>{{Cite web | url = https://www.s4me.info/threads/concerns-about-craniocervical-instability-surgery-in-me-cfs.9638/ | title = Concerns about craniocervical instability surgery in ME/CFS | website = Science for ME|language=en-US|access-date=2019-06-03}}</ref>

== Synonyms ==
* Syndrome of Occipitoatlantialaxial Hypermobility<ref name=":1" />
* Hypermobility of the Craniocervical Junction<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref>
* Craniocervical Junction Syndrome

== See also ==

* [[Atlantoaxial instability|Atlantoaxial instability (AAI)]]
* [[Neural strain]]
* [[Chiari malformation]]
* [[Ehlers-Danlos syndrome]]
* [[Intracranial hypertension]]
* [[Tethered cord syndrome]]

== Learn more ==
* [https://www.healthrising.org/blog/2019/02/27/brainstem-compression-chronic-fatigue-syndrome-me-cfs-fibromyalgia-pots-craniocervical-instability/ Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Spinal Series] - from Health Rising
* [https://www.healthrising.org/blog/2019/05/21/jennifer-brea-chronic-fatigue-mecfs-recovering-story/ Jennifer Brea’s Amazing ME/CFS Recovering Story: the Spinal Series – Pt. II] - From Health Rising
* [https://www.healthrising.org/treating-chronic-fatigue-syndrome/fibromyalgia-craniocervical-instability-survey-effectivness-survey/ ME/CFS and Fibromyalgia Craniocervical Instability Surgery Effectiveness Poll] - From Health Rising

== References ==
{{reflist}}
[[Category:Diagnoses]]

Craniocervical instability

2023-08-15T17:47:26Z

JenB:

[[File:Craniocervical-instability-CCI.png|thumb|'''Craniocervical instability''' 
MRI of a patient's cervical spine, showing C1 and C2 radiation necrosis with C1-2 instability, cancer in the nasopharynx, and narrowing of the central canal at C1. 
Source: Choi, Y., Woo, S. W., & Lee, J.H. (2018). [https://www.anesth-pain-med.org/m/journal/view.php?id=10.17085/apm.2018.13.4.383 Awake fiberoptic orotracheal intubation using a modified Guedel airway in a patient with craniocervical instability and an anticipated difficult airway: A case report]. Anesthesia and Pain Medicine, 13(4), 383-387. Fig 1.<ref name="Choi2018">{{Cite journal | last = Choi|first = Yongjoon | last2 = Woo | first2 = Sung-won | last3 = Lee | first3 = Ji Heui | date = 2018-10-31 | title = Awake fiberoptic orotracheal intubation using a modified Guedel airway in a patient with craniocervical instability and an anticipated difficult airway - A case report - | url = https://www.anesth-pain-med.org/m/journal/view.php?id=10.17085/apm.2018.13.4.383|journal=Anesthesia and Pain Medicine|volume=13|issue=4 | pages = 383–387|doi=10.17085/apm.2018.13.4.383|issn=2383-7977}}</ref> License: CC BY-NC-4.0]]
'''Craniocervical instability''' (CCI) is a pathological condition of increased mobility at the craniocervical junction, the area where the skull meets the spine. In CCI the ligamentous connections of the craniocervical junction can be stretched, weakened or ruptured.<ref name=":2">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Austin | first2 = Claudiu | last3 = Benzel | first3 = Edward | last4 = Bolognese | first4 = Paolo | last5 = Ellenbogen | first5 = Richard | last6 = Francomano | first6 = Clair A. | last7 = Ireton | first7 = Candace | last8 = Klinge | first8 = Petra | last9 = Koby | first9 = Myles | date = 2017 | title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1 | pages = 195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref> This can lead to stretching and/or compression of the [[Brainstem compression|brainstem]], upper [[spinal cord]], or cerebellum and result in myelopathy, neck pain and a range of other symptoms.<ref name=":11">{{Cite journal | last = Choi|first = Sung Ho | last2 = Lee | first2 = Sang Gu | last3 = Park | first3 = Chan Woo | last4 = Kim | first4 = Woo Kyung | last5 = Yoo | first5 = Chan Jong | last6 = Son | first6 = Seong | date = Apr 2013 | title = Surgical Outcomes and Complications after Occipito-Cervical Fusion Using the Screw-Rod System in Craniocervical Instability | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698232/|journal=Journal of Korean Neurosurgical Society|volume=53|issue=4 | pages = 223–227|doi=10.3340/jkns.2013.53.4.223|issn=2005-3711|pmc=3698232|pmid=23826478}}</ref>

CCI usually develops as a result of physical trauma such as a car accident, an inflammatory disease such as rheumatoid arthritis or a congenital disorder such as Down's syndrome.<ref name=":10">{{Cite journal | last = Ashafai|first = Nabeel S. | last2 = Visocchi | first2 = Massimiliano | last3 = Wąsik | first3 = Norbert | date = 2019 | title=Occipitocervical Fusion: An Updated Review | url =https://www.ncbi.nlm.nih.gov/pubmed/30610329|journal=Acta Neurochirurgica. Supplement|volume=125 | pages = 247–252|doi=10.1007/978-3-319-62515-7_35|issn=0065-1419|pmid=30610329}}</ref> More recently, physicians have reported an increased prevalence of CCI in patients with hereditary disorders of connective tissue such as Ehlers Danlos Syndromes (EDS).<ref name=":9">{{Cite journal | last = Henderson | first = Fraser C. | date = 2016 | title=Cranio-cervical Instability in Patients with Hypermobility Connective Disorders |url =https://www.omicsonline.org/open-access/craniocervical-instability-in-patients-with-hypermobility-connective-disorders-2165-7939-1000299.php?aid=71754|journal=Journal of Spine|language=en|volume=05|issue=02|doi=10.4172/2165-7939.1000299|issn=2165-7939}}</ref> There have also been anecdotal reports of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) who were later diagnosed with CCI (as well as [[tethered cord syndrome]]),<ref>{{Cite web | url = https://forums.phoenixrising.me/index.php?threads/have-you-ruled-out-chiari-as-a-cause-of-your-cfs.56908/ | title = Have you ruled out Chiari as a cause of your CFS | last = | first = | date = | website = Phoenix Rising| archive-url = | archive-date = |url-status = | access-date=}}</ref><ref>{{Cite web | url = https://medium.com/@jenbrea/cci-tethered-cord-series-e1e098b5edf | title = CCI + Tethered cord series | last = Brea | first = Jennifer | date = 2019-06-06 | website = Medium|language=en|access-date=2019-06-06}}</ref><ref>{{Cite web | url = https://www.mechanicalbasis.org/interviews.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-06}}</ref> although no scientific publication on this subject exists. It frequently co-occurs with [[atlantoaxial instability]] (AAI).{{Citation needed|reason= | date = 10 December 2019}}
== Symptoms ==
Symptoms of craniocervical instability include occipital [[headache]], [[neck pain]] and [[Nervous system|neurological]] abnormalities such as [[numbness]], [[paresis|motor weakness]], [[dizziness]], and [[gait instability]].<ref>{{Cite journal | last = Bobinski|first = Lukas | last2 = Levivier | first2 = Marc | last3 = Duff | first3 = John M. | date = Feb 2015 | title = Occipitoaxial spinal interarticular stabilization with vertebral artery preservation for atlantal lateral mass failure | url =https://www.ncbi.nlm.nih.gov/pubmed/25415481|journal=Journal of Neurosurgery Spine|volume=22|issue=2 | pages = 134–138|doi=10.3171/2014.10.SPINE14131|issn=1547-5646|pmid=25415481}}</ref><ref>{{Cite journal | last = O'Brien | first = Michael F. | last2 = Casey | first2 = Adrian T.H. | last3 = Crockard | first3 = Alan | last4 = Pringle | first4 = Jean | last5 = Stevens | first5 = John M. | date = 2002-10-15 | title = Histology of the craniocervical junction in chronic rheumatoid arthritis: a clinicopathologic analysis of 33 operative cases |url =https://www.ncbi.nlm.nih.gov/pubmed/12394902|journal=Spine|volume=27|issue=20 | pages = 2245–2254|doi=10.1097/01.BRS.0000029252.98053.43|issn=1528-1159|pmid=12394902}}</ref><ref>{{Cite journal | last = Young|first = Richard M. | last2 = Sherman | first2 = Jonathan H. | last3 = Wind | first3 = Joshua J. | last4 = Litvack | first4 = Zachary | last5 = O'Brien | first5 = Joseph | date = Aug 2014 | title = Treatment of craniocervical instability using a posterior-only approach: report of 3 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/24785968|journal=Journal of Neurosurgery. Spine|volume=21|issue=2 | pages = 239–248|doi=10.3171/2014.3.SPINE13684|issn=1547-5646|pmid=24785968}}</ref><ref>{{Cite journal | last = Botelho|first = Ricardo V. | last2 = Neto | first2 = Eliseu B. | last3 = Patriota | first3 = Gustavo C. | last4 = Daniel | first4 = Jefferson W. | last5 = Dumont | first5 = Paulo A.S. | last6 = Rotta | first6 = José M. | date = Oct 2007 | title = Basilar invagination: craniocervical instability treated with cervical traction and occipitocervical fixation. Case report | url = https://www.ncbi.nlm.nih.gov/pubmed/17933321|journal=Journal of Neurosurgery. Spine|volume=7|issue=4 | pages = 444–449|doi=10.3171/SPI-07/10/444|issn=1547-5654|pmid=17933321}}</ref><ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Henderson | first2 = Fraser C. | last3 = Wilson | first3 = William A. | last4 = Mark | first4 = Alexander S. | last5 = Koby | first5 = Myles | date = Jan 2018 | title = Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review | url =https://www.ncbi.nlm.nih.gov/pubmed/28258417|journal=Neurosurgical Review|volume=41|issue=1 | pages = 149–163|doi=10.1007/s10143-017-0830-3|issn=1437-2320|pmc=5748419|pmid=28258417|quote=|via=}}</ref> Patients sometimes describe the feeling that their head is too heavy for their neck to support (“bobble-head”).<ref name=":9" /> No particular symptom is mandatory for a diagnosis of CCI and each symptom listed might have a cause other than CCI.

Other symptoms reported in patients with CCI include:
* [[Muscle weakness]],<ref name=":0">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Francomano | first2 = C.A. | last3 = Koby | first3 = M. | last4 = Tuchman | first4 = K. | last5 = Adcock | first5 = J. | last6 = Patel | first6 = S. | date = 2019-01-09 | title = Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization | url =https://doi.org/10.1007/s10143-018-01070-4|journal=Neurosurgical Review|volume=92|issue= | pages = 915–936|language=en|doi=10.1007/s10143-018-01070-4|issn=1437-2320}}</ref> [[numbness|numbness,]]<ref name=":1">{{Cite journal | last = Francomano|first = Clair A. | last2 = McDonnell | first2 = Nazli B. | last3 = Nishikawa | first3 = Misao | last4 = Bolognese | first4 = Paolo A. | last5 = Milhorat | first5 = Thomas H. | date = 2007-12-01 | title = Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and Chiari malformation Type I in patients with hereditary disorders of connective tissue | url =https://thejns.org/view/journals/j-neurosurg-spine/7/6/article-p601.xml|journal=Journal of Neurosurgery: Spine|language=en-US|volume=7|issue=6 | pages = 601–609|doi=10.3171/SPI-07/12/601}}</ref><ref name=":2" /> [[paralysis]], [[paresthesia]]s<ref name=":0" /><ref name=":4">{{Cite web | url = https://search.proquest.com/openview/34b3b18a8854c04ffa0fc50273d68313/1?pq-origsite=gscholar&cbl=47886 | title = MRI video diagnosis and surgical therapy of soft tissue trauma to the craniocervical junction - ProQuest | website = search.proquest.com|language=en|access-date=2019-06-01}}</ref><ref name=":5">{{Cite journal | last = Rebbeck|first = Trudy | last2 = Liebert | first2 = Ann | date = 2014-12-01 | title = Clinical management of cranio-vertebral instability after whiplash, when guidelines should be adapted: A case report | url = http://www.sciencedirect.com/science/article/pii/S1356689X14000101|journal=Manual Therapy|volume=19|issue=6 | pages = 618–621|doi=10.1016/j.math.2014.01.009|issn=1356-689X}}</ref><ref name=":6">{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult Hypermobility of the Craniocervical Junction: A Case Report and Review | url =https://www.jospt.org/doi/full/10.2519/jospt.2011.3305|journal=Journal of Orthopaedic & Sports Physical Therapy|language=en|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=0190-6011}}</ref>
* Poor [[proprioception]],<ref name=":7">{{Cite journal | last = Bergholm|first = Ulla | last2 = Johansson | first2 = Bengt H. | last3 = Johansson | first3 = Hakan | date = 2004-01-01 | title = New Diagnostic Tools Can Contribute to Better Treatment of Patients with Chronic Whiplash Disorders |url =https://doi.org/10.3109/J180v03n02_02|journal=Journal of Whiplash & Related Disorders|volume=3|issue=2 | pages = 5–19|doi=10.3109/J180v03n02_02|issn=1533-2888}}</ref> [[impaired coordination]], [[gait]] changes<ref name=":0" /><ref name=":7" />
* [[Dizziness]], [[vertigo|vertigo,]]<ref name=":0" /><ref name=":2" /><ref name=":7" /><ref name=":4" /><ref name=":6" /><ref name=":5" /> syncope,<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":7" /> nausea<ref name=":1" /><ref name=":2" />
* [[Tension-type headache|Headache behind the eyes]],<ref name=":6" /> [[stiff neck|neck stiffness]], torticollis,<ref name=":7" /><ref>{{Cite journal | last = Ghanem|first = Ismat | last2 = El Hage | first2 = Samer | last3 = Rachkidi | first3 = Rami | last4 = Kharrat | first4 = Khalil | last5 = Dagher | first5 = Fernand | last6 = Kreichati | first6 = Gabi | date = 2008-03-01 | title = Pediatric cervical spine instability | url = https://online.boneandjoint.org.uk/doi/full/10.1007/s11832-008-0092-2|journal=Journal of Children's Orthopaedics|volume=2|issue=2 | pages = 71–84|doi=10.1007/s11832-008-0092-2|issn=1863-2521|pmc=2656787|pmid=19308585}}</ref> posterior scalp irritation,<ref name=":7" /> [[facial pain]]
* Apnea,<ref>{{Cite journal | last = Janjua | first = M. Burhan | last2 = Hwang | first2 = Steven W. | last3 = Samdani | first3 = Amer F. | last4 = Pahys | first4 = Joshua M. | last5 = Baaj | first5 = Ali A. | last6 = Härtl | first6 = Roger | last7 = Greenfield | first7 = Jeffrey P. | date = 2019-01-01 | title = Instrumented arthrodesis for non-traumatic craniocervical instability in very young children | url =https://doi.org/10.1007/s00381-018-3876-9|journal=Child's Nervous System|language=en|volume=35|issue=1 | pages = 97–106|doi=10.1007/s00381-018-3876-9|issn=1433-0350}}</ref><ref name=":1" /><ref name=":3">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Austin | first2 = Claudiu | last3 = Benzel | first3 = Edward | last4 = Bolognese | first4 = Paolo | last5 = Ellenbogen | first5 = Richard | last6 = Francomano | first6 = Clair A. | last7 = Ireton | first7 = Candace | last8 = Klinge | first8 = Petra | last9 = Koby | first9 = Myles | date = 2017 | title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1 | pages = 195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref> [[dyspnea]] (shortness of breath),<ref name=":0" /><ref name=":1" /> and [[dysphagia]] (difficulty swallowing)<ref name=":1" /><ref name=":2" />
* [[visual dysfunction|Visual disturbance]]s<ref name=":4" /> downward [[nystagmus]] (irregular eye movements),<ref name=":1" /><ref name=":7" /> [[tinnitus]]<ref>{{Cite journal | last = Montazem|first = Abbas | authorlink = | date = 2000 | title = Secondary tinnitus as a symptom of instability in the upper cervical spine: Operative management | url = https://www.tinnitusjournal.com/articles/secondary-tinnitus-as-a-symptom-ofinstability-of-the-upper-cervical-spineoperative-management.pdf | journal=International Tinnitus Journal|volume=6|issue=2 | pages = 130-3|pmid=14689631|quote=|via=}}</ref><ref name=":4" />
* [[Fatigue]],<ref name=":0" /><ref name=":14">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Henderson | first2 = Fraser C. | last3 = Wilson | first3 = William A. | last4 = Mark | first4 = Alexander S. | last5 = Koby | first5 = Myles | date = 2018-01-01 | title = Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review | url =https://doi.org/10.1007/s10143-017-0830-3|journal=Neurosurgical Review|language=en|volume=41|issue=1 | pages = 149–163|doi=10.1007/s10143-017-0830-3|issn=1437-2320|pmc=5748419|pmid=28258417}}</ref><ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Wilson | first2 = William A. | last3 = Mott | first3 = Stephen | last4 = Mark | first4 = Alexander | last5 = Schmidt | first5 = Kristi | last6 = Berry | first6 = Joel K. | last7 = Vaccaro | first7 = Alexander | last8 = Benzel | first8 = Edward | date = 2010-07-16 | title = Deformative stress associated with an abnormal clivo-axial angle: A finite element analysis |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940090/|journal=Surgical Neurology International|volume=1|doi=10.4103/2152-7806.66461|issn=2152-7806|pmc=2940090|pmid=20847911}}</ref> [[Sleep dysfunction]],<ref name=":0" /><ref name=":4" /> [[Cognitive dysfunction|cognitive impairment]],<ref name=":4" /> and [[Memory problems|memory loss]].

== Risk factors and comorbidities ==
Established risk factors for CCI include physical [[trauma]], infection, [[inflammation|inflammatory]] disease, neoplasms and congenital disorders.<ref name=":10" /><ref name=":12">{{Cite journal | last = Sapkas | first = George | last2 = Papadakis | first2 = Stamatios A | last3 = Segkos | first3 = Dimitrios | last4 = Kateros | first4 = Konstantinos | last5 = Tsakotos | first5 = George | last6 = Katonis | first6 = Pavlos | date = 2011-06-02 | title = Posterior Instrumentation for Occipitocervical Fusion | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139273/|journal=The Open Orthopaedics Journal|volume=5 | pages = 209–218|doi=10.2174/1874325001105010209|issn=1874-3250|pmc=3139273|pmid=21772931}}</ref>

More recently, physicians have reported an increased prevalence of CCI in patients with hereditary [[connective tissue disorder]]s.<ref name=":9" /> According to Brodbelt & Flint, however, an "increased range of joint movement, caused by ligamentous laxity, is not the same as [[spinal instability]] resulting from trauma or major inflammatory arthropathies such as (historically) [[rheumatoid arthritis]]."<ref name=":19">{{Cite journal | last = Brodbelt | first = Andrew R. | last2 = Flint | first2 = Graham | date = Aug 2017 | title = Ehlers Danlos, complex Chiari and cranio-cervical fixation: how best should we treat patients with hypermobility? | url = https://www.ncbi.nlm.nih.gov/pubmed/28961036|journal=British Journal of Neurosurgery|volume=31|issue=4 | pages = 397–398|doi=10.1080/02688697.2017.1386282|issn=1360-046X|pmid=28961036|pmc=|quote=|via=}}</ref> Others have argued that "pathological instability at the cranio-cervical junction has not been clearly established in the literature for the [[joint hypermobility]] population."<ref name=":9" />

{| class="wikitable"
|'''Cause of instability'''
|'''Example'''
|-
|Physical trauma<ref>{{Cite journal | last = Ghatan | first = Saadi | last2 = Newell | first2 = David W. | last3 = Grady | first3 = M. Sean | last4 = Mirza | first4 = Sohail K. | last5 = Chapman | first5 = Jens R. | last6 = Mann | first6 = Frederick A. | last7 = Ellenbogen | first7 = Richard G. | date = Aug 2004 | title = Severe posttraumatic craniocervical instability in the very young patient. Report of three cases |url =https://www.ncbi.nlm.nih.gov/pubmed/16206980|journal=Journal of Neurosurgery|volume=101|issue=1 Suppl | pages = 102–107|doi=10.3171/ped.2004.101.2.0102|issn=0022-3085|pmid=16206980}}</ref>
|Car accident<ref>{{Cite journal | last = Uribe | first = Juan S. | last2 = Ramos | first2 = Edwin | last3 = Baaj | first3 = Ali | last4 = Youssef | first4 = A. Samy | last5 = Vale | first5 = Fernando L. | date = Dec 2009 | title = Occipital cervical stabilization using occipital condyles for cranial fixation: technical case report | url = https://www.ncbi.nlm.nih.gov/pubmed/19934947|journal=Neurosurgery|volume=65|issue=6| pages = E1216–1217; discussion E1217|doi=10.1227/01.NEU.0000349207.98394.FA|issn=1524-4040|pmid=19934947}}</ref><ref>{{Cite journal | last = Volle | first = E. | last2 = Montazem | first2 = A. | date = Jan 2001 | title = MRI video diagnosis and surgical therapy of soft tissue trauma to the craniocervical junction | url =https://www.ncbi.nlm.nih.gov/pubmed/11209518|journal=Ear, Nose, & Throat Journal|volume=80|issue=1 | pages = 41–44, 46–48|issn=0145-5613|pmid=11209518}}</ref>, blow to the head.<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref>
|-
|Infection & inflammatory disease
|Upper respiratory infection<ref>{{Cite journal | last = Hettiaratchy|first = Shehan | last2 = Ning | first2 = Chou | last3 = Sabin | first3 = Ian | date = 1998-07-01 | title = Nontraumatic Atlanto-occipital and Atlantoaxial Rotatory Subluxation: Case Report | url = https://academic.oup.com/neurosurgery/article/43/1/162/2856810|journal=Neurosurgery|language=en|volume=43|issue=1 | pages = 162–164|doi=10.1097/00006123-199807000-00110|issn=0148-396X}}</ref><ref>{{Cite journal | last = Washington | first = Eleby R. | date = Mar 1959 | title = Non-Traumatic Atlanto-Occipital and Atlanto-Axial Dislocation: A Case Report | url = https://journals.lww.com/jbjsjournal/Citation/1959/41020/Non_Traumatic_Atlanto_Occipital_and_Atlanto_Axial.15.aspx|journal=JBJS|language=en-US|volume=41|issue=2 | pages = 341–344|issn=0021-9355}}</ref>, Rheumatoid arthritis<ref>{{Cite journal | last = O'Brien | first = Michael F. | last2 = Casey | first2 = Adrian T.H. | last3 = Crockard | first3 = Alan | last4 = Pringle | first4 = Jean | last5 = Stevens | first5 = John M. | date = 2002-10-15 | title = Histology of the craniocervical junction in chronic rheumatoid arthritis: a clinicopathologic analysis of 33 operative cases |url =https://www.ncbi.nlm.nih.gov/pubmed/12394902|journal=Spine|volume=27|issue=20 | pages = 2245–2254|doi=10.1097/01.BRS.0000029252.98053.43|issn=1528-1159|pmid=12394902}}</ref>, tuberculosis<ref>{{Cite journal | last = Chaudhary|first = Kshitij | last2 = Potdar | first2 = Prabodhan | last3 = Bapat | first3 = Mihir | last4 = Rathod | first4 = Ashok | last5 = Laheri | first5 = Vinod | date = 2012-06-15 | title = Structural odontoid lesions in craniovertebral tuberculosis: a review of 15 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/22261632|journal=Spine|volume=37|issue=14| pages = E836–843|doi=10.1097/BRS.0b013e31824a4c8f|issn=1528-1159|pmid=22261632}}</ref>
|-
|Neoplasms
|Tumors<ref name=":12" /> such as haemangioma, aneurysmal bone cyst
|-
|Congenital
|Down’s syndrome<ref>{{Cite journal | last = Hankinson | first = Todd C. | last2 = Anderson | first2 = Richard C.E. | date = Mar 2010 | title = Craniovertebral junction abnormalities in Down syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/20173525|journal=Neurosurgery|volume=66|issue=3 Suppl | pages = 32–38|doi=10.1227/01.NEU.0000365803.22786.F0|issn=1524-4040|pmid=20173525}}</ref>, os odontoideum<ref>{{Cite journal | last = Zhao|first = Deng | last2 = Wang | first2 = Shenglin | last3 = Passias | first3 = Peter G. | last4 = Wang | first4 = Chao | date = May 2015 | title = Craniocervical instability in the setting of os odontoideum: assessment of cause, presentation, and surgical outcomes in a series of 279 cases |url =https://www.ncbi.nlm.nih.gov/pubmed/25635883|journal=Neurosurgery|volume=76|issue=5 | pages = 514–521|doi=10.1227/NEU.0000000000000668|issn=1524-4040|pmid=25635883}}</ref>, dwarfism
|-
|Hereditary connective tissue disorder
|Ehlers Danlos Syndromes<ref name=":0" /><ref name=":1" />
|-
|Fluoroquinolones
|Connective tissue weakening<ref name=":20">{{Cite journal | last = Etminan | first = M. | authorlink = | last2 = Sodhi | first2 = M. | authorlink2 = | last3 = Ganjizadeh-Zavareh | first3 = S. | author-link3 = | last4 = Carleton | first4 = B. | author-link4 = | last5 = Kezouh | first5 = A. | author-link5 = | last6 = Brophy | first6 = J.M. | author-link6 = | date = 2019-09-17 | title = Oral Fluoroquinolones and Risk of Mitral and Aortic Regurgitation | url =https://www.sciencedirect.com/science/article/pii/S0735109719359789|journal=Journal of the American College of Cardiology|language=en|volume=74|issue=11 | pages = 1444–1450|doi=10.1016/j.jacc.2019.07.035|issn=0735-1097|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref>{{Cite journal | last = Demetrious | first = James S. | date = 2018-07-09 | title = Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? | url = https://doi.org/10.1186/s12998-018-0193-z|journal=Chiropractic & Manual Therapies|volume=26|issue=1 | pages = 22|doi=10.1186/s12998-018-0193-z|issn=2045-709X}}</ref>, tendon ruptures<ref>{{Cite journal | last = Stephenson | first = Anne L. | last2 = Wu | first2 = Wei | last3 = Cortes | first3 = Daniel | last4 = Rochon | first4 = Paula A. | date = Sep 2013 | title = Tendon Injury and Fluoroquinolone Use: A Systematic Review | url =https://pubmed.ncbi.nlm.nih.gov/23888427/#|journal=Drug Safety|volume=36|issue=9 | pages = 709–721|doi=10.1007/s40264-013-0089-8|issn=1179-1942|pmid=23888427}}</ref>
|}
It is not unusual for CCI to co-occur with other structural neurological abnormalities such as [[atlantoaxial instability]] (AAI) and [[chiari malformation]] (CM).<ref>{{Cite journal | last = Camino Willhuber | first = Gaston O. | last2 = Bosio | first2 = Santiago T. | last3 = Puigdevall | first3 = Miguel H. | last4 = Halliburton | first4 = Carolina | last5 = Sola | first5 = Carlos A. | last6 = Maenza | first6 = Ruben A. | date = Jan 2017 | title = Craniocervical spinal instability after type 1 Arnold Chiari decompression: a case report | url = https://www.ncbi.nlm.nih.gov/pubmed/27258364|journal=Journal of Pediatric Orthopedics. Part B|volume=26|issue=1 | pages = 80–85|doi=10.1097/BPB.0000000000000346|issn=1473-5865|pmid=27258364}}</ref><ref name=":0" />

== Diagnosis ==
{{Video|id=https://youtu.be/MsYDA3SXTkg|service=youtube|dimensions=550|description=Dr. Paolo Bolognese discusses methods of imaging and measurement for diagnosis.|alignment=right|urlargs=}}
The diagnosis of CCI is based on symptom presentation, a supportive history, demonstrable neurological findings and abnormal imaging.

=== Imaging ===
CCI is typically diagnosed via a cervical [[Magnetic resonance imaging|MRI]], whether supine or upright. If supine, a 3 Tesla MRI is preferred over a 1.5 Tesla. Most neurosurgeons prefer upright MRI with flexion and extension.{{citation needed | date = 2021 | reason=source not meeting scientific guidelines}}<ref>{{Cite web | url = https://www.mechanicalbasis.org/diagnosis.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-02}}</ref> According to Henderson FC, “ventral [[brainstem]] compression may exist in flexion of the cervical spine, but appear normal on routine imaging.”<ref name=":9" />

{| class="wikitable"
!Imaging
!Sensitive for
|-
|Upright MRI with flexion/extension
|Horizontal instability
|-
|CT scan with rotation
|Rotational instability
|-
|Invasive cervical traction (ICT) with fluoroscopy
|Vertical instability
|}

=== Measurements ===
More than twenty radiological measurements have been proposed or used in the diagnosis of CCI. However, three measurements are most commonly used: the [[Grabb-Oakes measurement|Grabb-Oakes]] line, which measures ventral brainstem compression; the [[Clivo-axial angle|Clivo-Axial Angle (CXA)]], which measures brainstem deformity by the [[odontoid]] process; and the Basion Dens Interval, which measures vertical instability ([[cranial settling]]). According to a 2013 consensus statement on the assessment of CCI, a CXA of 135 degrees or less should be considered as "potentially pathological."<ref name=":13">{{Cite web | url = https://bobbyjonescsf.org/csf-video/review-colloq-2014/ | title = REVIEW OF THE 2013 CSF RESEARCH COLLOQUIUM & CONSENSUS ON CRANIOCERVICAL INSTABILITY – Bobby Jones CSF | last = CSF|first = Bobby Jones {{!}}|language=en-US|access-date=2019-09-18}}</ref> as it is reported to be uncommon in the healthy population.<ref>{{Cite journal | last = Batista | first = Ulysses C. | last2 = Joaquim | first2 = Andrei F. | last3 = Fernandes | first3 = Yvens B. | last4 = Mathias | first4 = Roger N. | last5 = Ghizoni | first5 = Enrico | last6 = Tedeschi | first6 = Helder | date = Apr 2015 | title = Computed tomography evaluation of the normal craniocervical junction craniometry in 100 asymptomatic patients |url =https://www.ncbi.nlm.nih.gov/pubmed/25828499|journal=Neurosurgical Focus|volume=38|issue=4| pages = E5|doi=10.3171/2015.1.FOCUS14642|issn=1092-0684|pmid=25828499}}</ref><ref>{{Cite journal | last = Botelho|first = Ricardo Vieira | last2 = Ferreira | first2 = Edson Dener Zandonadi | date = Oct 2013 | title = Angular craniometry in craniocervical junction malformation | url =https://www.ncbi.nlm.nih.gov/pubmed/23640096|journal=Neurosurgical Review|volume=36|issue=4 | pages = 603–610; discussion 610|doi=10.1007/s10143-013-0471-0|issn=1437-2320|pmc=3910287|pmid=23640096}}</ref><ref>{{Cite journal | last = Bundschuh|first = C | last2 = Modic | first2 = Mt | last3 = Kearney | first3 = F | last4 = Morris | first4 = R | last5 = Deal | first5 = C | date = 1988-07-01 | title = Rheumatoid arthritis of the cervical spine: surface-coil MR imaging | url =https://www.ajronline.org/doi/abs/10.2214/ajr.151.1.181|journal=American Journal of Roentgenology|volume=151|issue=1 | pages = 181–187|doi=10.2214/ajr.151.1.181|issn=0361-803X}}</ref> Others have argued that these radiological measurements are "not accepted internationally as indicating instability."<ref name=":19" />
{| class="wikitable"
|+
!Measurement
!Units
!Description
! scope="col" style="width: 75px;" | Normal Range
! scope="col" style="width: 75px;" | Borderline Range
! scope="col" style="width: 75px;" | Pathological Range
! scope="col" style="width: 75px;" | Alternate Ranges
!Instability Measured
!Pathology Measured
!Refs
|-
|'''Clivo-axial angle (CXA)'''
|Degrees
|Angle between clivus line and the posterior axial line
|170 -150
|149 -136
|≤ 135
|
|More sensitive for horizontal
|Brainstem deformity
|<ref name="Bolognese2014yt">{{Cite web | last = Bolognese | first = Paolo | authorlink = | date = 2014 | title = Videoed Presentation at: ASAP Chiari & Syringomyelia Conference Paolo Bolognese, MD "Complex Chiari. Timecode 14:28 | url = https://www.youtube.com/watch?v=uiyk0Qbx2TQ&t=14m28s | website = YouTube|quote=|via=}}</ref>
|-
|'''Grabb-Oakes'''
|mm
|Distance from the dura to the line drawn from the basion to the posterior inferior edge of the C2 vertebra
|< 6
|≥ 6 and < 9
|≥ 9
|Some use pathological ≥ 8
|More sensitive for horizontal
|Brainstem compression
|<ref>{{Cite web | last = Bolognese | first = Paolo | authorlink = | date = April 12, 2018 | title = Videoed presentation at: EDS Awareness Educational Series. Timecodes: 49:30 and 53:47 | url = https://www.youtube.com/watch?v=MsYDA3SXTkg&t=49m30s | website = YouTube|quote=|via=}}</ref><ref name=":9" />
|-
|'''Basion-Axial Interval (BAI)'''
|mm
|Distance from tip of basion to posterior axial line
|< 12
|
|≥ 12
|
|
|
|<ref name=":15">{{Cite web | last = Henderson | first = Fraser | authorlink = | date = | title = Videoed presentation at: Chiari & Syringomyelia Foundation, Patient Conference of Action, June 24, 2018. Timecode: 10:34. | url = https://www.youtube.com/watch?list=WL&v=sEi9AlHQTJc&t=10m34s|journal=|volume=|issue=| pages=|quote=|via=}}</ref>
|-
|'''Basion-Dens interval (BDI)'''
|mm
|Vertical distance between the basion and the dens
|< 12
|
|≥ 12
|Some use pathological ≥ 10
|Vertical
|Cranial settling
|<ref name=":15" /><ref name=":9" />
|-
|'''Translational BAI'''
|mm
|Change in BAI between flexion and extension positions of the head
|< 1
|≥ 1 and ≤ 2
|> 2
|For surgery > 4 needed
|Horizontal
|Skull sliding over spine
|<ref>{{Cite journal | last = Henderson | first = Fraser C. | last2 = Francomano | first2 = C.A. | last3 = Koby | first3 = M. | last4 = Tuchman | first4 = K. | last5 = Adcock | first5 = J. | last6 = Patel | first6 = S. | date = 2019-01-09 | title = Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization | url =https://doi.org/10.1007/s10143-018-01070-4|journal=Neurosurgical Review|language=en|doi=10.1007/s10143-018-01070-4|issn=1437-2320}}</ref><ref name=":0" />
|-
|'''Translational BDI'''
|mm
|Change in BDI between flexion and extension positions of the head
|
|
|
|
|
|
|
|-
|'''Dynamic BDI'''
|mm
|Change in BDI value when the head is pulled upward with traction force of typically up to 35 lbs
|
|
|
|
|Vertical
|Cranial settling
|
|-
|'''Dens Over Chamberlain'''
|mm
|How far tip of the dens extends above Chamberlain's line
|< 2
|≥ 2 and ≤ 3
|≥ 3
|
|Vertical
|Basilar invagination
|<ref>{{Cite web | last = Hain | first = Timothy C. | authorlink = | date = | title = Basilar Invagination, Basilar Impression and Atlantoaxial Subluxation | url =https://www.dizziness-and-balance.com/disorders/central/cerebellar/basilar%20invagination.htm | website = dizziness-and-balance.com|quote=|via=}}</ref>{{citation needed | date = 2022))
|}
Some of the measurement ranges in the above table are also to be found in the 2nd International CSF Dynamics Symposium Consensus Statement (2013).<ref name=":13" />

=== Traction ===
Manual traction, halo and invasive cervical traction may be used to aid in the diagnosis of CCI. Symptomatic improvement with traction can help determine whether a patient with abnormal measurements will benefit from craniocervical fusion surgery.

== Treatment ==
{{Video|id=https://youtu.be/sEi9AlHQTJc|service=youtube|dimensions=550|description=Dr. Fraser Henderson presents the results a five-year follow-up study.|alignment=right|urlargs=}}
=== Conservative treatment ===
Traditional “conservative” treatments for CCI include rest, pain management, upper cervical chiropractic treatment, and bracing with a cervical collar.<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref> Although, in most cases these offer little relief.

Other experimental treatments for CCI include prolotherapy and stem cell therapy.

=== Surgery ===
If non-invasive treatments for CCI fail to work, occipito-cervical fusion (OCF) can be considered.<ref name=":0" /> OCF is a surgery that aims at a biomechanical stabilization of the craniocervical junction. Patients with objective radiological findings, a clinical picture supportive of the diagnosis, a positive response to traction, and who are significantly impaired may be candidates for this surgery. A common method involves internal fixation of the upper spine to the skull by mechanical rods and screws. (However, rod-wire, rigid rod-screws, occipital hooks and cervical claws are all methods currently in use.<ref name=":16">{{Cite journal | last = Resnick|first = Daniel K. | last2 = Patel | first2 = Nirav J. | last3 = Lall | first3 = Rishi | date = 2010-11-01 | title = A Review of Complications Associated With Craniocervical Fusion Surgery | url = https://academic.oup.com/neurosurgery/article/67/5/1396/2563905|journal=Neurosurgery|language=en|volume=67|issue=5 | pages = 1396–1403|doi=10.1227/NEU.0b013e3181f1ec73|issn=0148-396X}}</ref>) During surgery, titanium hardware is used to fixate the occiput, axis and atlas (i.e., C0 to C2) while rib graft, cadaver bone graft or synthetic bone is used to help the bones fuse together. Wire methods are less biomechanically stable than rod methods and have high rates of dural laceration.<ref name=":16" /> Screw and rod fixation methods have lower complication rates and higher rates of successful fusion.<ref name=":18" /> Fusion rates across all hardware methods range from 89 to 100%.<ref name=":16" /> When cervical instability is present below C2, additional vertebrae may also be fused.

==== Outcomes, risks & complications ====
Little research on outcomes exists. In a small case study of 20 patients, the five-year outcome of OCF was generally favorable with most patients experiencing symptom relief post-surgery.<ref name=":0" /> In this study, following 20 EDS patients five years free O-2 fusion, most reported they were satisfied with the surgery and experienced significant improvements in symptoms such as vertigo, headaches, imbalance, dysarthria, dizziness, and frequent daytime urination. There was, however, only a small increase in objective outcomes such as work resumption, with 60% of patients remaining unable to work or go to school. Participants attributed this to other EDS comorbidities such as POTS, Mast Cell Activation Syndrome, and additional spinal problems.<ref name=":0" />

The complications of OCF can be serious<ref>{{Cite journal | last = Garrido|first = Ben J. | last2 = Sasso | first2 = Rick C. | date = Jan 2012 | title = Occipitocervical fusion | url =https://www.ncbi.nlm.nih.gov/pubmed/22082624|journal=The Orthopedic Clinics of North America|volume=43|issue=1 | pages = 1–9, vii|doi=10.1016/j.ocl.2011.08.009|issn=1558-1373|pmid=22082624}}</ref> and occur in an estimated 7% to 33% of patients.<ref name=":10" /><ref name=":18">{{Cite journal | last = Winegar | first = Corbett D. | last2 = Lawrence | first2 = James P. | last3 = Friel | first3 = Brian C. | last4 = Fernandez | first4 = Carmella | last5 = Hong | first5 = Joseph | last6 = Maltenfort | first6 = Mitchell | last7 = Anderson | first7 = Paul A. | last8 = Vaccaro | first8 = Alexander R. | date = Jul 2010 | title = A systematic review of occipital cervical fusion: techniques and outcomes |url =https://www.ncbi.nlm.nih.gov/pubmed/20594011|journal=Journal of Neurosurgery. Spine|volume=13|issue=1 | pages = 5–16|doi=10.3171/2010.3.SPINE08143|issn=1547-5646|pmid=20594011}}</ref><ref name=":11" /><ref>{{Cite journal | last = Ando|first = Kei | last2 = Imagama | first2 = Shiro | last3 = Ito | first3 = Zenya | last4 = Kobayashi | first4 = Kazuyoshi | last5 = Yagi | first5 = Hideki | last6 = Shinjo | first6 = Ryuichi | last7 = Hida | first7 = Tetsuro | last8 = Ito | first8 = Kenyu | last9 = Ishikawa | first9 = Yoshimoto | date = Jun 2017 | title = Minimum 5-year Follow-up Results for Occipitocervical Fusion Using the Screw-Rod System in Craniocervical Instability | url = https://www.ncbi.nlm.nih.gov/pubmed/28525489|journal=Clinical Spine Surgery|volume=30|issue=5| pages = E628–E632|doi=10.1097/BSD.0000000000000199|issn=2380-0194|pmid=28525489}}</ref><ref name=":16" /> Common complications include screw failure, wound infection, dural tear and cerebrospinal fluid leakage<ref name=":11" /> In some cases revision surgery is needed to treat infection or to remove hardware. Severe complications can include meningitis and accidental injury of the vertebral artery by misplaced screws.<ref name=":17">{{Cite journal | last = Nockels | first = Russ P. | last2 = Shaffrey | first2 = Christopher I. | last3 = Kanter | first3 = Adam S. | last4 = Azeem | first4 = Syed | last5 = York | first5 = Julie E. | date = Aug 2007 | title = Occipitocervical fusion with rigid internal fixation: long-term follow-up data in 69 patients |url =https://www.ncbi.nlm.nih.gov/pubmed/17688049|journal=Journal of Neurosurgery. Spine|volume=7|issue=2 | pages = 117–123|doi=10.3171/SPI-07/08/117|issn=1547-5654|pmid=17688049}}</ref>

A meta-study of 2274 procedures across 22 studies<ref name=":16" /> found the following complication rates:

{| class="wikitable"
!Complication type
!Prevalence rate
|-
|Hardware failure after fusion non-union
|7%
|-
|Wound infection
|3.8%-11%
|-
|Vertebral artery damage
|1.3%-4.1%
|-
|Dural tears
|0% to 4.2%
|}
Meta-studies place the rate of death from fusion surgery at 0-0.6%.<ref name=":16" /><ref name=":18" />

==== Side effects ====
OCF causes a substantial reduction in the neck’s range of motion, estimated at approximately 40% of total cervical flexion–extension.<ref name=":8">{{Cite book | last = Ashafai|first = Nabeel S. | last2 = Visocchi | first2 = Massimiliano | last3 = Wąsik | first3 = Norbert | date = 2019 | editor-last = Visocchi|editor-first = Massimiliano | title = Occipitocervical Fusion: An Updated Review | url =https://doi.org/10.1007/978-3-319-62515-7_35|series=Acta Neurochirurgica Supplement|language=en|location=Cham| publisher = Springer International Publishing | pages = 247–252|doi=10.1007/978-3-319-62515-7_35|isbn=9783319625157}}</ref>

==== Cost ====
OCF is estimated to cost tens of thousands of dollars, although some insurance schemes fully cover the cost of surgery depending on the country located and neurosurgeons involved.

=== Experimental treatments ===
* '''[[Stem cell therapy]]:''' Some clinics offer stem cell therapy in order to regenerate the area, ligaments, connective and other tissues that may be damaged in the area, e.g. Centeno-Schultz Clinic.<ref>https://centenoschultz.com/cervical-joint-degeneration/</ref>

*'''[[Platelet-rich plasma therapy|Platelet-Rich Plasma therapy]] (PRP therapy)''': Some clinics offer PRP therapy in order to help the body regenerate the area, e.g. Regenexx clinic.<ref>https://regenexx.com/blog/candidacy-for-ccj-instability-procedure/</ref><ref>https://www.nwrestorativemedicine.com/pain-solutions/neck-pain/</ref>

*'''[[Percutaneous implantation of the CCJ ligaments]]''' (PICL): A non-surgical treatment involving injecting your own bone marrow concentrate to strengthen ligaments.<ref name="picl">https://centenoschultz.com/craniocervical-instability-cci/</ref>

== Dysautonomia and CCI in EDS ==
As CCI can lead to a compression of the brainstem, a number of experts believe it contributes to autonomic symptoms such as orthostatic tachycardia, dizziness and pre-/syncope that are frequently seen in patients with Ehlers Danlos Syndromes (EDS). In a 2007 influential paper Milhorat et al. followed-up on patients with Chiari malformation who did not improve with treatment and surgery. The authors discovered that many of these patients suffered from EDS and had other structural abnormalities at the upper spine such as CCI and cranial settling. Milhorat et al. speculated that the resulting compression of the brainstem might be the cause of the autonomic and other symptoms these patients were suffering from.<ref>{{Cite journal | last = Milhorat | first = Thomas H. | last2 = Bolognese | first2 = Paolo A. | last3 = Nishikawa | first3 = Misao | last4 = McDonnell | first4 = Nazli B. | last5 = Francomano | first5 = Clair A. | date = Dec 2007 | title = Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue | url =https://www.ncbi.nlm.nih.gov/pubmed/18074684|journal=Journal of Neurosurgery. Spine|volume=7|issue=6 | pages = 601–609|doi=10.3171/SPI-07/12/601|issn=1547-5654|pmid=18074684}}</ref> Neurosurgeons and other EDS specialists have expounded on the connection between CCI and forms of dysautonomia such as postural orthostatic tachycardia syndrome (POTS) in a number of conference presentations. <ref>[https://www.youtube.com/watch?time_continue=735&v=857Jsjsqxjw Craniocervical Instability (Dr Henderson the 2012 EDNF Confrence).] Minute 12.10. </ref><ref>[https://www.youtube.com/watch?v=ntD9NRIvEJ0 Dr Milhorat from The Chiari Institute at the 2005 ASAP.]</ref><ref name=":13" />

== Mechanical basis theory ==
Dozens of ME/CFS patients diagnosed with CCI (some also had EDS) reported to have experienced remarkable improvements and even remission of their ME/CFS symptoms following OCF-surgery.<ref>{{Cite web | url = https://www.mechanicalbasis.org/interviews.html | title = Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS | website = MEchanical Basis|language=en|access-date=2019-06-06}}</ref><ref>{{Cite web | url = https://medium.com/@jenbrea/health-update-3-my-me-is-in-remission-dd575e650f71 | title = Health update #3: My ME is in remission | last = Brea | first = Jennifer | date = 2019-05-20 | website = Medium|access-date=2019-06-03}}</ref> They speculate that mechanical compression of the brainstem due to CCI, or other underlying structural conditions, have the potential to cause characteristic ME/CFS symptoms such as post-exertional malaise, although there have not been any studies regarding this particular theory.
Some have raised concerns about CCI surgery in patients with ME/CFS given the lack of research on OCF in this patient population.<ref>{{Cite web | url = https://www.s4me.info/threads/concerns-about-craniocervical-instability-surgery-in-me-cfs.9638/ | title = Concerns about craniocervical instability surgery in ME/CFS | website = Science for ME|language=en-US|access-date=2019-06-03}}</ref>

== Synonyms ==
* Syndrome of Occipitoatlantialaxial Hypermobility<ref name=":1" />
* Hypermobility of the Craniocervical Junction<ref>{{Cite journal | last = Mathers | first = K. Sean | last2 = Schneider | first2 = Michael | last3 = Timko | first3 = Michael | date = Jun 2011 | title = Occult hypermobility of the craniocervical junction: a case report and review | url =https://www.ncbi.nlm.nih.gov/pubmed/21628827|journal=The Journal of Orthopaedic and Sports Physical Therapy|volume=41|issue=6 | pages = 444–457|doi=10.2519/jospt.2011.3305|issn=1938-1344|pmid=21628827}}</ref>
* Craniocervical Junction Syndrome

== See also ==

* [[Atlantoaxial instability|Atlantoaxial instability (AAI)]]
* [[Neural strain]]
* [[Chiari malformation]]
* [[Ehlers-Danlos syndrome]]
* [[Intracranial hypertension]]
* [[Tethered cord syndrome]]

== Learn more ==
* [https://www.healthrising.org/blog/2019/02/27/brainstem-compression-chronic-fatigue-syndrome-me-cfs-fibromyalgia-pots-craniocervical-instability/ Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Spinal Series] - from Health Rising
* [https://www.healthrising.org/blog/2019/05/21/jennifer-brea-chronic-fatigue-mecfs-recovering-story/ Jennifer Brea’s Amazing ME/CFS Recovering Story: the Spinal Series – Pt. II] - From Health Rising
* [https://www.healthrising.org/treating-chronic-fatigue-syndrome/fibromyalgia-craniocervical-instability-survey-effectivness-survey/ ME/CFS and Fibromyalgia Craniocervical Instability Surgery Effectiveness Poll] - From Health Rising

== References ==
{{reflist}}
[[Category:Diagnoses]]

Hypoxia

2023-08-15T17:42:49Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia can be caused by insufficient blood supply or by inflammation<ref>{{Cite journal|title=Inflammatory Hypoxia: Role of Hypoxia-Inducible Factor|date=2005-02-19|url=https://www.tandfonline.com/doi/full/10.4161/cc.4.2.1407|journal=Cell Cycle|volume=4|issue=2|pages=255–257|last=Karhausen|first=Jörn|last2=Haase|first2=Volker H.|last3=Colgan|first3=Sean P.|language=en|doi=10.4161/cc.4.2.1407|issn=1538-4101}}</ref>.

Hypoxia at altitude iscaused by pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found reduced blood flow to the [[heart]]<ref>{{Cite journal | last = Patrick Neary|first = J. | last2 = Roberts | first2 = Andy D.W. | last3 = Leavins | first3 = Nina | last4 = Harrison | first4 = Michael F. | last5 = Croll | first5 = James C. | last6 = Sexsmith | first6 = James R. | date = Nov 2008 | title = Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1475-097X.2008.00822.x|journal=Clinical Physiology and Functional Imaging|volume=28|issue=6 | pages = 364–372|doi=10.1111/j.1475-097x.2008.00822.x|issn=1475-0961}}</ref><ref>{{Cite journal | last = Peterson | first = PK | last2 = Sirr | first2 = SA | last3 = Grammith | first3 = FC | last4 = Schenck | first4 = CH | last5 = Pheley | first5 = AM | last6 = Hu | first6 = S | last7 = Chao | first7 = C C | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC368231/|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>, [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, even in the absence of [[postural orthostatic tachycardia]] or [[Neurally mediated hypotension|neurally-mediated hypotension]]; cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref>; as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>. Peripheral endothelial dysfunction has also been found.<ref name="endothelial2020">{{Cite journal | last = Scherbakov|first = Nadja | authorlink = | last2 = Szklarski | first2 = Marvin | author-link2 = | last3 = Hartwig | first3 = Jelka | author-link3 = | last4 = Sotzny | first4 = Franziska | author-link4 = Franziska Sotzny | last5 = Lorenz | first5 = Sebastian | author-link5 = | last6 = Meyer | first6 = Antje | authorlink6 = Antje Meyer | last7 = Grabowski | first7 = Patricia | last8 = Doehner | first8 = Wolfram | last9 = Scheibenbogen | first9 = Carmen | authorlink9 = Carmen Scheibenbogen | date = 2020 | title=Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ehf2.12633|journal=ESC Heart Failure|language=en|volume=7|issue=3|pages=1064–1071|doi=10.1002/ehf2.12633|issn=2055-5822|pmc = 7261521|pmid=32154656|access-date=|quote=|via=}}</ref>

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|date=Jan 2015|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|volume=3|pages=1|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|language=English|doi=10.2147/HP.S60872|issn=2324-1128}}</ref>

[[Creatine]], elevated in #MECFS patients<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>, is protective against hypoxia<ref>{{Cite journal|title=Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship|date=1999-01-16|url=https://www.sciencedirect.com/science/article/pii/S0006899398011317|journal=Brain Research|volume=816|issue=1|pages=124–130|last=Balestrino|first=Maurizio|last2=Rebaudo|first2=Renata|last3=Lunardi|first3=Gianluigi|doi=10.1016/S0006-8993(98)01131-7|issn=0006-8993}}</ref>.

Hypoxia can induce mitochondrial damage and dysfunction<ref>{{Cite journal|title=Hypoxia–reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C|date=2005-05-15|url=https://www.sciencedirect.com/science/article/pii/S0891584905000353|journal=Free Radical Biology and Medicine|volume=38|issue=10|pages=1311–1322|last=Dhar-Mascareño|first=Manya|last2=Cárcamo|first2=Juan M.|last3=Golde|first3=David W.|doi=10.1016/j.freeradbiomed.2005.01.017|issn=0891-5849}}</ref>, which has been found in ME/CFS patients<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref><ref name=":02">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref>.

=== In Long COVID ===

=== In mast cell activation syndrome ===

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

== References ==
*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T11:10:16Z

JenB:

Hypoxia

2023-08-15T10:49:56Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia is caused by a pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found reduced blood flow to the [[heart]]<ref>{{Cite journal | last = Patrick Neary|first = J. | last2 = Roberts | first2 = Andy D.W. | last3 = Leavins | first3 = Nina | last4 = Harrison | first4 = Michael F. | last5 = Croll | first5 = James C. | last6 = Sexsmith | first6 = James R. | date = Nov 2008 | title = Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1475-097X.2008.00822.x|journal=Clinical Physiology and Functional Imaging|volume=28|issue=6 | pages = 364–372|doi=10.1111/j.1475-097x.2008.00822.x|issn=1475-0961}}</ref><ref>{{Cite journal | last = Peterson | first = PK | last2 = Sirr | first2 = SA | last3 = Grammith | first3 = FC | last4 = Schenck | first4 = CH | last5 = Pheley | first5 = AM | last6 = Hu | first6 = S | last7 = Chao | first7 = C C | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC368231/|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>, [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, even in the absence of [[postural orthostatic tachycardia]] or [[Neurally mediated hypotension|neurally-mediated hypotension]]; cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref>; as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>. Peripheral endothelial dysfunction has also been found.<ref name="endothelial2020">{{Cite journal | last = Scherbakov|first = Nadja | authorlink = | last2 = Szklarski | first2 = Marvin | author-link2 = | last3 = Hartwig | first3 = Jelka | author-link3 = | last4 = Sotzny | first4 = Franziska | author-link4 = Franziska Sotzny | last5 = Lorenz | first5 = Sebastian | author-link5 = | last6 = Meyer | first6 = Antje | authorlink6 = Antje Meyer | last7 = Grabowski | first7 = Patricia | last8 = Doehner | first8 = Wolfram | last9 = Scheibenbogen | first9 = Carmen | authorlink9 = Carmen Scheibenbogen | date = 2020 | title=Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ehf2.12633|journal=ESC Heart Failure|language=en|volume=7|issue=3|pages=1064–1071|doi=10.1002/ehf2.12633|issn=2055-5822|pmc = 7261521|pmid=32154656|access-date=|quote=|via=}}</ref>

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|date=Jan 2015|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|volume=3|pages=1|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|language=English|doi=10.2147/HP.S60872|issn=2324-1128}}</ref>

[[Creatine]], elevated in #MECFS patients<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>, is protective against hypoxia<ref>{{Cite journal|title=Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship|date=1999-01-16|url=https://www.sciencedirect.com/science/article/pii/S0006899398011317|journal=Brain Research|volume=816|issue=1|pages=124–130|last=Balestrino|first=Maurizio|last2=Rebaudo|first2=Renata|last3=Lunardi|first3=Gianluigi|doi=10.1016/S0006-8993(98)01131-7|issn=0006-8993}}</ref>.

Hypoxia can induce mitochondrial damage and dysfunction<ref>{{Cite journal|title=Hypoxia–reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C|date=2005-05-15|url=https://www.sciencedirect.com/science/article/pii/S0891584905000353|journal=Free Radical Biology and Medicine|volume=38|issue=10|pages=1311–1322|last=Dhar-Mascareño|first=Manya|last2=Cárcamo|first2=Juan M.|last3=Golde|first3=David W.|doi=10.1016/j.freeradbiomed.2005.01.017|issn=0891-5849}}</ref>, which has been found in ME/CFS patients<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref><ref name=":02">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref>.

=== In Long COVID ===

=== In mast cell activation syndrome ===

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T10:39:44Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia is caused by a pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref> as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>.

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|date=Jan 2015|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|volume=3|pages=1|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|language=English|doi=10.2147/HP.S60872|issn=2324-1128}}</ref>

[[Creatine]], elevated in #MECFS patients<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>, is protective against hypoxia<ref>{{Cite journal|title=Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship|date=1999-01-16|url=https://www.sciencedirect.com/science/article/pii/S0006899398011317|journal=Brain Research|volume=816|issue=1|pages=124–130|last=Balestrino|first=Maurizio|last2=Rebaudo|first2=Renata|last3=Lunardi|first3=Gianluigi|doi=10.1016/S0006-8993(98)01131-7|issn=0006-8993}}</ref>.

Hypoxia can induce mitochondrial damage and dysfunction<ref>{{Cite journal|title=Hypoxia–reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C|date=2005-05-15|url=https://www.sciencedirect.com/science/article/pii/S0891584905000353|journal=Free Radical Biology and Medicine|volume=38|issue=10|pages=1311–1322|last=Dhar-Mascareño|first=Manya|last2=Cárcamo|first2=Juan M.|last3=Golde|first3=David W.|doi=10.1016/j.freeradbiomed.2005.01.017|issn=0891-5849}}</ref>, which has been found in ME/CFS patients<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref><ref name=":02">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref>.

=== In Long COVID ===

=== In mast cell activation syndrome ===

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T10:31:30Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia is caused by a pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref> as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>.

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|date=Jan 2015|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|volume=3|pages=1|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|language=English|doi=10.2147/HP.S60872|issn=2324-1128}}</ref>

=== In Long COVID ===

=== In mast cell activation syndrome ===

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T10:18:57Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia is caused by a pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref> as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>.

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

=== In Long COVID ===

=== In mast cell activation syndrome ===

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T10:17:40Z

JenB:

'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either ''generalized'', affecting the whole body, or ''local'', affecting a region of the body.

Hypoxia is caused by a pressure gradient difference between the atmospheric oxygen and the oxygen in the lungs, or the oxygen in the lungs and the oxygen in other parts of the body. Hypoxia is frequently experienced as altitude sickness.

=== In ME/CFS ===

Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref> as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>.

Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> Mast cells, increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref>

==Learn more==

*[http://science.sciencemag.org/content/352/6281/54 Hypoxia as a therapy for mitochondrial disease]

==See also==

*[[Hyperbaric oxygen therapy]]

Hypoxia

2023-08-15T10:14:40Z

JenB:

Hypoxia

2023-08-15T10:09:16Z

JenB:

Atlantoaxial instability

2023-08-14T17:55:03Z

JenB:

'''Atlantoaxial instability''' or '''Atlanto-axial instability''' '''(AAI)''' is characterized by excessive movement at the junction between the atlas (C1) and axis (C2) as a result of either a bone or ligament abnormality.<ref name="emedicine" /><ref name="Lacy2019" />

==Causes ==
Atlantoaxial instability can be caused by hereditary conditions including Marfan Syndrome, neurofibromatosis, connective tissue conditions like [[rheumatoid arthritis]],or [[Ehlers-Danlos Syndrome]]s (EDS), as a result of physical trauma, or infection.<ref name="emedicine"/><ref name="Henderson2020">https://link.springer.com/article/10.1007/s10143-020-01345-9</ref> It has been associated with Down syndrome, Morquio syndrome,<ref name="Li2013">{{Cite journal | last = Li | first = Ming-Feng | last2 = Chiu | first2 = Pao-Chin | last3 = Weng | first3 = Mei-Jui | last4 = Lai | first4 = Ping-Hong | date = 2010-12-13 | title = Atlantoaxial Instability and Cervical Cord Compression in Morquio Syndrome | url =https://jamanetwork.com/journals/jamaneurology/fullarticle/801729 | journal = Archives of Neurology|language=en | volume = 67 | issue = 12 | pages = 1530–1530|doi=10.1001/archneurol.2010.308|issn=0003-9942}}</ref> [[Marfan syndrome]],<ref name=":3">{{Cite journal | last = MacKenzie | first = James MacKintosh | last2 = Rankin | first2 = Rosslyn | date = Dec 2003 | title = Sudden Death Due to Atlantoaxial Subluxation in Marfan Syndrome | url =https://journals.lww.com/amjforensicmedicine/Abstract/2003/12000/Sudden_Death_Due_to_Atlantoaxial_Subluxation_in.12.aspx | journal = The American Journal of Forensic Medicine and Pathology|language=en-US | volume = 24 | issue = 4 | pages = 369|doi=10.1097/01.paf.0000097853.26115.bb|issn=0195-7910|pmc=|pmid=|quote=|access-date=|via=}}</ref> and [[Ehlers-Danlos syndrome]].<ref>{{Cite web | url = https://europepmc.org/article/med/8596160 | title = Europe PMC | website = europepmc.org | access-date = 2019-12-10}}</ref><ref name="Henderson2017">{{Cite journal | last = Henderson | first = Fraser C. | last2 = Austin | first2 = Claudiu | last3 = Benzel | first3 = Edward | last4 = Bolognese | first4 = Paolo | last5 = Ellenbogen | first5 = Richard | last6 = Francomano | first6 = Clair A. | last7 = Ireton | first7 = Candace | last8 = Klinge | first8 = Petra | last9 = Koby | first9 = Myles | date = 2017 | title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549 | journal = American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en | volume = 175 | issue = 1 | pages = 195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref><ref>{{Cite journal | last = Castori | first = Marco | last2 = Morlino | first2 = Silvia | last3 = Ghibellini | first3 = Giulia | last4 = Celletti | first4 = Claudia | last5 = Camerota | first5 = Filippo | last6 = Grammatico | first6 = Paola | date = 2015 | title=Connective tissue, Ehlers–Danlos syndrome(s), and head and cervical pain | url =https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31426 | journal = American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en | volume = 169 | issue = 1 | pages = 84–96|doi=10.1002/ajmg.c.31426|issn=1552-4876}}</ref><ref>{{Cite journal | last = Lane | first = D. | date = 2006-08-01 | title = Anaesthetic Implications of Vascular Type Ehlers-Danlos Syndrome | url =https://doi.org/10.1177/0310057X0603400412 | journal = Anaesthesia and Intensive Care|language=en | volume = 34 | issue = 4 | pages = 501–505|doi=10.1177/0310057X0603400412|issn=0310-057X}}</ref><ref>{{Cite journal | last = Dordoni | first = Chiara | last2 = Ciaccio | first2 = Claudia | last3 = Venturini | first3 = Marina | last4 = Calzavara‐Pinton | first4 = Piergiacomo | last5 = Ritelli | first5 = Marco | last6 = Colombi | first6 = Marina | date = 2016 | title=Further delineation of FKBP14-related Ehlers–Danlos syndrome: A patient with early vascular complications and non-progressive kyphoscoliosis, and literature review | url =https://www.onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.37728 | journal = American Journal of Medical Genetics Part A|language=en | volume = 170 | issue = 8 | pages = 2031–2038|doi=10.1002/ajmg.a.37728|issn=1552-4833}}</ref><ref>{{Cite journal | last = Giunta | first = Cecilia | last2 = Baumann | first2 = Matthias | last3 = Fauth | first3 = Christine | last4 = Lindert | first4 = Uschi | last5 = Abdalla | first5 = Ebtesam M. | last6 = Brady | first6 = Angela F. | last7 = Collins | first7 = James | last8 = Dastgir | first8 = Jahannaz | last9 = Donkervoort | first9 = Sandra | date = Jan 2018 | title = A cohort of 17 patients with kyphoscoliotic Ehlers–Danlos syndrome caused by biallelic mutations in FKBP14 : expansion of the clinical and mutational spectrum and description of the natural history | url = https://www.nature.com/articles/gim201770 | journal = Genetics in Medicine|language=en | volume = 20 | issue = 1 | pages = 42–54|doi=10.1038/gim.2017.70|issn=1530-0366|pmc=|pmid=|quote=|access-date=|via=}}</ref><ref>{{Cite web | url = https://europepmc.org/article/med/2387821 | title = Europe PMC | website = europepmc.org | access-date = 2019-12-10}}</ref><ref>{{Cite journal | last = Galan | first = Enrique | last2 = Kousseff | first2 = Boris G. | date = 1995-04-01 | title = Peripheral neuropathy in Ehlers-Danlos syndrome | url =http://www.sciencedirect.com/science/article/pii/088789949500003X | journal = Pediatric Neurology | volume = 12 | issue = 3 | pages = 242–245|doi=10.1016/0887-8994(95)00003-X|issn=0887-8994}}</ref><ref>{{Cite journal | last = Wills | first = Brian P.D. | last2 = Dormans | first2 = John P. | date = Apr 2006 | title = Nontraumatic Upper Cervical Spine Instability in Children | url =https://journals.lww.com/jaaos/Citation/2006/04000/Nontraumatic_Upper_Cervical_Spine_Instability_in.5.aspx | journal = JAAOS - Journal of the American Academy of Orthopaedic Surgeons|language=en-US | volume = 14 | issue = 4 | pages = 233|issn=1067-151X| doi = | pmc = | pmid = | quote = |access-date=|via=}}</ref><ref>{{Cite journal | last = Herzka | first = Andrea | last2 = Sponseller | first2 = Paul D. | last3 = Pyeritz | first3 = Reed E. | date = 2000-02-15 | title = Atlantoaxial Rotatory Subluxation in Patients With Marfan Syndrome: A Report of Three Cases |url =https://journals.lww.com/spinejournal/Abstract/2000/02150/Atlantoaxial_Rotatory_Subluxation_in_Patients_With.22.aspx | journal = Spine|language=en-US | volume = 25 | issue = 4 | pages = 524|issn=0362-2436}}</ref>

AAI often co-occurs with [[craniocervical instability]] (CCI).

In individuals without predisposing conditions, it is thought to be extremely rare.<ref name="Lacy2019">{{Cite book | last = Lacy | first = Jordan | last2 = Gillis | first2 = Christopher C. | date = 2019 | title=Atlantoaxial Instability | url = http://www.ncbi.nlm.nih.gov/books/NBK519563/|location=Treasure Island (FL)| publisher = StatPearls Publishing|pmid=30137847}}</ref>

== Symptoms ==

* Neck pain<ref name="Lacy2019" />
* Neck stiffness, torticollis<ref name="Cohen1998">{{Cite journal | last = Cohen | first = William I. | date = 1998-02-01 | title = Atlantoaxial Instability: What's Next? | url = https://jamanetwork.com/journals/jamapediatrics/fullarticle/189216 | journal = Archives of Pediatrics & Adolescent Medicine|language=en | volume = 152 | issue = 2 | pages = 119–122|doi=10.1001/archpedi.152.2.119|issn=1072-4710}}</ref>
* Spasticity<ref name="Lacy2019" />
* Radicular symptoms<ref name="Lacy2019" />
* Lack of coordination<ref name="Lacy2019" />
* Clumsiness<ref name="Lacy2019" />
* Gait changes, difficulty with gait<ref name="Lacy2019" /><ref name="Cohen1998" />
* Sensory deficits<ref name="Lacy2019" />
* Neurogenic bladder<ref name="Lacy2019" />
* Clonus, hyperreflexia<ref name="Lacy2019" /><ref name="Cohen1998" />
* Paraplegia, quadriplegia<ref name="Lacy2019" />
* Muscle weakness, which is not a constant feature<ref name="Henderson2017" />
* Blurred vision<ref name=":3" />
* Occipital headache<ref name=":3" />
Symptoms can often be exacerbated by rotation of the neck.

== Risk factors and causes ==

=== Congenital causes ===

=== Rheumatoid arthritis ===
Chronic inflammation can cause laxity and stretching of the transverse ligament, the formation of a pannus, as well as bone erosion.<ref name="Lacy2019" />

=== Grisel’s syndrome ===
Grisel’s syndrome is AAI that occurs following inflammation of the soft tissue as a consequence of surgery or infection,<ref name="emedicine" /> frequently an upper respiratory infection. It is primarily seen in patients ages 5-12 but can also be seen in adults.<ref name="emedicine">{{Cite web | date = 2019-11-10 | title = Atlantoaxial Instability: Background, Pathophysiology, Etiology | url = https://emedicine.medscape.com/article/1265682-overview#a3}}</ref> It usually presents with torticollis, neck pain, neck tilt, and stiffness.<ref name="Fernandez">{{Cite journal | last = Fernández Cornejo | first = Víctor J. | last2 = Martínez-Lage | first2 = Juan F. | last3 = Piqueras | first3 = Claudio | last4 = Gelabert | first4 = Amparo | last5 = Poza | first5 = Máximo | date = 2003-06-01 | title = Inflammatory atlanto-axial subluxation (Grisel's syndrome) in children: clinical diagnosis and management | url = https://doi.org/10.1007/s00381-003-0749-6 | journal = Child's Nervous System|language=en | volume = 19 | issue = 5 | pages = 342–347|doi=10.1007/s00381-003-0749-6|issn=1433-0350}}</ref> It can often be treated with conservative therapies such as physical therapy, traction, immobilization, anti-inflammatories and treatment of any underlying infection.<ref name="Fernandez" />

A handful of cases of concomitant non-traumatic CCI and AAI following upper respiratory infections have also been documented.<ref name="Washington1998">{{Cite journal | title = Nontraumatic Atlanto-occipital and Atlantoaxial Rotatory Subluxation: Case Report | url = https://academic.oup.com/neurosurgery/article/43/1/162/2856810 | journal = Neurosurgery | date = 1998-07-01|issn=0148-396X | pages = 162–164 | volume = 43 | issue = 1|doi=10.1097/00006123-199807000-00110|language=en | first = Shehan | last = Hettiaratchy | first2 = Chou | last2 = Ning | first3 = Ian | last3 = Sabin}}</ref><ref>{{Cite journal | title = Non-Traumatic Atlanto-Occipital and Atlanto-Axial Dislocation: A Case Report | url = https://journals.lww.com/jbjsjournal/Citation/1959/41020/Non_Traumatic_Atlanto_Occipital_and_Atlanto_Axial.15.aspx | journal = JBJS | date = Mar 1959|issn=0021-9355 | pages = 341–344 | volume = 41 | issue = 2|language=en-US| first = Eleby R. | last = Washington | last2 = | first2 = | doi = | pmc = | pmid = | quote = |access-date=|via=}}</ref>

== Co-morbid conditions ==
AAI can cause vertebrobasilar insufficiency.<ref name="Vinchon">{{Cite journal | last = Vinchon | first = Matthieu | last2 = Assaker | first2 = Richard | last3 = Leclerc | first3 = Xavier | last4 = Lejeune | first4 = Jean-Paul | date = 1995-04-01 | title = Vertebrobasilar Insufficiency Resulting from Traumatic Atlantoaxial InstabilityCase Report | url = https://academic.oup.com/neurosurgery/article/36/4/839/2753933 | journal = Neurosurgery|language=en | volume = 36 | issue = 4 | pages = 839–841|doi=10.1227/00006123-199504000-00027|issn=0148-396X}}</ref>

== Diagnosis ==
AAI diagnosis is based on a neurological exam, reported symptoms, and radiological measurements, generally a CTSCAN with rotation. An atlantodental (or atlantodens or atlas-dens) interval (ADI) of greater than 3 mm in adults and of greater than 5 mm in children as measured on plain radiography is considered indicative of AAI. The ADI is the distance between the odontoid process and the posterior border of the anterior arch of the atlas. An abnormal degreeof rotation of the atlas (C1) on C2 has also been determined to indicate instability.

== Treatment==

== See also ==
* [[Craniocervical instability]]

== Learn more ==

== References ==
{{Reflist}}

[[Category:Diagnoses]]

Talk:Long COVID

2023-08-13T03:02:43Z

JenB:

==Long COVID studies to add ==

*May, 2023, Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection <ref>https://jamanetwork.com/journals/jama/fullarticle/2805540?guestAccessKey=1fbcad3a-e2ab-492f-8dcc-0288c178fb94&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=052523</ref>
*Oct, 2022 Survey of Long COVID patients response to Nattokinase <ref> https://twitter.com/organichemusic/status/1579052732484575233</ref>

*Aug, 2022, Degradative Effect of Nattokinase on Spike Protein of SARS-CoV-2 <ref>https://www.mdpi.com/1420-3049/27/17/5405/htm</ref>

*Sep 2021, Post-COVID syndrome. A case series and comprehensive review<ref name="Anaya2021">{{Cite journal | last = Anaya | first = Juan-Manuel | last2 = Rojas | first2 = Manuel | last3 = Salinas | first3=Martha L. | last4 = Rodríguez | first4 = Yhojan | last5 = Roa | first5 = Geraldine|last6 = Lozano | first6 = Marcela | last7 = Rodríguez-Jiménez | first7 = Mónica | last8 = Montoya | first8 = Norma | last9 = Zapata | first9 = Elizabeth| date = 2021-09-10 | title = Post-COVID syndrome. A case series and comprehensive review | url =https://www.sciencedirect.com/science/article/pii/S1568997221002226|journal=Autoimmunity Reviews|language=en|pages=102947|doi=10.1016/j.autrev.2021.102947|issn=1568-9972}}</ref>
*May 2021, Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments<ref name="Yong2021">{{Cite journal | last =Yong | first = Shin Jie | author-link = | date = 2021 | title=Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments|url=https://doi.org/10.1080/23744235.2021.1924397|journal=Infectious Diseases|volume=53|issue=10|pages=737–754|doi=10.1080/23744235.2021.1924397|issn=2374-4235|pmc=PMC8146298|pmid=34024217|access-date=|quote=|via=}}</ref>

*Apr 2021, Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms<ref name="Andrade2021">{{Cite journal | last =Silva Andrade | first = Bruno|author-link = | last2 = Siqueira | first2 = Sérgio|author-link2 = | last3 = de Assis Soares | first3=Wagner Rodrigues | author-link3 = | last4 = de Souza Rangel | first4 = Fernanda | author-link4 = | last5 = Santos | first5 = Naiane Oliveira | authorlink5 = |last6 = dos Santos Freitas | first6 = Andria | authorlink6 = | last7 = Ribeiro da Silveira | first7 = Priscila | last8 = Tiwari | first8 = Sandeep | last9 = Alzahrani | first9 = Khalid J. | date = Apr 2021 | title = Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms|url=https://www.mdpi.com/1999-4915/13/4/700|journal=Viruses|language=en|volume=13|issue=4|pages=700|doi=10.3390/v13040700|pmc=|pmid=|access-date=|quote=|via=}}</ref>

*Sep 2021, Long-term side effects and lingering symptoms post COVID-19 recovery<ref name="Zarei2021">{{Cite journal | last =Zarei | first = Mohammad | authorlink = | last2 = Bose | first2 = Deepanwita|author-link2 = | last3 = Nouri-Vaskeh | first3 = Masoud | author-link3 = | last4 = Tajiknia | first4 = Vida | author-link4 = | last5 = Zand | first5 = Ramin | authorlink5 = |last6 = Ghasemi | first6 = Mehdi | authorlink6 = | date = | title =Long-term side effects and lingering symptoms post COVID-19 recovery|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/rmv.2289|journal=Reviews in Medical Virology|language=en|volume=|issue=| pages = e2289|doi=10.1002/rmv.2289|issn=1099-1654|pmc=|pmid=|access-date=|quote=|via=}}</ref>

*Jan 2021, Long Covid-19: Proposed Primary Care Clinical Guidelines for Diagnosis and Disease Management<ref name="SisoAlmiral2021">{{Cite journal | last =Sisó-Almirall | first = Antoni | authorlink = | last2 = Brito-Zerón | first2=Pilar | author-link2 = | last3 = Conangla Ferrín | first3 = Laura | author-link3 = | last4 = Kostov | first4 = Belchin | author-link4 = | last5 = Moragas Moreno | first5 = Anna | authorlink5 = |last6 = Mestres | first6 = Jordi | authorlink6 = | last7 = Sellarès | first7 = Jaume | last8 = Galindo | first8 = Gisela | last9 = Morera | first9 = Ramon | date = Jan 2021 | title = Long Covid-19: Proposed Primary Care Clinical Guidelines for Diagnosis and Disease Management|url=https://www.mdpi.com/1660-4601/18/8/4350|journal=International Journal of Environmental Research and Public Health|language=en|volume=18|issue=8|pages=4350|doi=10.3390/ijerph18084350|pmc=|pmid=|access-date=|quote=|via=}}</ref>
:"the overlap of the signs and symptoms they present with processes like fibromyalgia, chronic fatigue syndrome, or multiple chemical sensitivity is, medically, incontestable."

*Aug 2021, Post-COVID Syndrome: Incidence, Clinical Spectrum, and Challenges for Primary Healthcare Professionals<ref name="Pavli2021">{{Cite journal | last =Pavli | first = Androula|author-link = | last2 = Theodoridou | first2 = Maria|author-link2 = | last3 = Maltezou | first3 = Helena C. | author-link3 = | date = Aug 2021 | title = Post-COVID Syndrome: Incidence, Clinical Spectrum, and Challenges for Primary Healthcare Professionals|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093949/|journal=Archives of Medical Research|volume=52|issue=6|pages=575–581|doi=10.1016/j.arcmed.2021.03.010|issn=0188-4409|pmc=8093949|pmid=33962805|access-date=|quote=|via=}}</ref>

:"There are five categories of long COVID-19 syndrome: Type 1 includes patients with varying duration of recovery that directly relates to the severity of infection, organ damage, and underlying medical conditions; Type 2 is characterized by symptoms persisting six weeks from the onset of illness; Type 3 shows a period of quiescence or nearly full recovery after initial infection, followed by a recurrence of symptoms that persist for at least three months (Type 3A) or at least six months (Type 3B); Type 4 includes patients who are initially asymptomatic at the time of a positive SARS-CoV-2 test but develop symptoms one to three months (Type 4A) or at least three months later (Type 4B), that persist for varying lengths of period; and Type 5 includes patients who have no or few symptoms at the time of a positive SARS-CoV-2 test and experience sudden death within the next 12 months"

*Feb 2021, A review of persistent post-COVID syndrome (PPCS)<ref name="Oronsky2021">{{Cite journal | last =Oronsky | first = Bryan | last2 = Larson | first2=Christopher | last3=Hammond | first3=Terese C. | last4 = Oronsky | first4 = Arnold | last5 = Kesari | first5 = Santosh|last6 = Lybeck | first6 = Michelle | last7 = Reid | first7 = Tony R. | date = 2021-02-20 | title = A Review of Persistent Post-COVID Syndrome (PPCS)|url=https://doi.org/10.1007/s12016-021-08848-3|journal=Clinical Reviews in Allergy & Immunology|language=en|doi=10.1007/s12016-021-08848-3|issn=1559-0267|pmc=PMC7896544|pmid=33609255}}</ref>

:"we have coined the umbrella term “persistent post-COVID syndrome” (PPCS) to describe the morbid post-ICU course of COVID survivors"

:"compensatory anti-inflammatory response syndrome (CARS) occurs that leads to postinfectious/posttraumatic immunosuppression [8]. The purpose of the CARS response, a mirror-imaged counter-regulation to SIRS or systemic inflammatory response syndrome, is to dampen the proinflammatory state, prevent maladaptive multiple-organ dysfunction [9], and govern the return to immunologic homeostasis or normalcy [10]."

:"excessive release of inflammatory cytokines such as interleukins 1, 6, 8, 17, and 1β, monocyte chemoattractant protein-1, and tissue necrosis factor α [11] collectively known as “cytokine storm”"
:"Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19"

*Nov 2020, Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19<ref name="Ludvigsson2021">{{Cite journal | last =Ludvigsson | first=Jonas F. | date = 2021 | title = Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15673|journal=Acta Paediatrica|language=en|volume=110|issue=3 | pages = 914–921|doi=10.1111/apa.15673|issn=1651-2227|pmc=PMC7753397|pmid=33205450}}</ref>
:The five children with potential long COVID had a median age of 12 years (range 9–15) and four were girls. They had symptoms for 6–8 months after their clinical diagnoses of COVID-19. None were hospitalised at diagnosis, but one was later admitted for peri-myocarditis. All five children had fatigue, dyspnoea, heart palpitations or chest pain, and four had headaches, difficulties concentrating, muscle weakness, dizziness and sore throats. Some had improved after 6–8 months, but they all suffered from fatigue and none had fully returned to school. The systematic review identified 179 publications and 19 of these were deemed relevant and read in detail. None contained any information on long COVID in children.
[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 01:42, September 30, 2021 (UTC)

===References ===
{{Reflist|talk}}}

===Old ===

== Date Order -- [[User:Loopy|Loopy]] ([[User talk:Loopy|talk]]) 17:52, November 6, 2020 (UTC) ==

The dates are in the wrong order. Should be oldest to newest.
:I've sorted this for Notable studies. ~[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 23:40, November 6, 2020 (UTC)

Tethered cord syndrome

2021-08-11T19:44:21Z

JenB:Updated symptoms

{{Cleanup|reason=Image copyright issues|date =5 August, 2018}}{{Video|id=https://www.youtube.com/watch?v=zpSXSMPiMI8|service=youtube|dimensions=550|description=|alignment=right|urlargs=}}
'''Tethered cord syndrome''' is a neurological disorder caused by tissue attachments that limit the movement of the spinal cord within the spinal column. It can be congenital or acquired and appear in childhood or adulthood. It is considered progressive.<ref>{{Cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Tethered-Spinal-Cord-Syndrome-Information-Page|title=Tethered Spinal Cord Syndrome Information Page {{!}} National Institute of Neurological Disorders and Stroke|website=www.ninds.nih.gov|access-date=2019-07-26}}</ref>[[File:Tethered cord drawing.png|thumb]]It causes spinal cord hypoperfusion, electrophysical changes and metabolic changes, including impaired glucose metabolism.<ref name=":2">{{Cite journal|last=Colohan|first=Austin R. T.|last2=Zouros|first2=Alexander|last3=Siddiqi|first3=Javed|last4=Yamada|first4=Shoko M.|last5=Yamada|first5=Brian S.|last6=Pezeshkpour|first6=Gholam|last7=Won|first7=Daniel J.|last8=Yamada|first8=Shokei|date=2007-08-01|title=Pathophysiology of tethered cord syndrome and similar complex disorders|url=https://thejns.org/view/journals/neurosurg-focus/23/2/foc-07_08_e6.xml|journal=Neurosurgical Focus|language=en-US|volume=23|issue=2|pages=1–10|doi=10.3171/FOC-07/08/E6|issn=1092-0684}}</ref><ref>{{Cite journal|last=Colohan|first=Austin R. T.|last2=Yamada|first2=Shokei|date=2009-01-01|title=Tethered Cord Syndrome|url=https://thejns.org/view/journals/j-neurosurg-spine/10/1/article-p79.xml|journal=Journal of Neurosurgery: Spine|language=en-US|volume=10|issue=1|pages=79–80|doi=10.3171/2008.10.SPI15714L}}</ref><ref>{{Cite journal|last=Sullivan|first=Stephen|last2=Park|first2=Paul|last3=Stetler|first3=William R.|date=2010-07-01|title=Pathophysiology of adult tethered cord syndrome: review of the literature|url=https://thejns.org/view/journals/neurosurg-focus/29/1/2010.3.focus1080.xml|journal=Neurosurgical Focus|language=en-US|volume=29|issue=1|pages=E2|doi=10.3171/2010.3.FOCUS1080|issn=1092-0684}}</ref>

There are a range of conditions associated with tethered cord. The most dramatic is spina bifida, where the spinal cord does not complete it's development and is visible on the outside of the body.<ref>{{Cite web|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spina-Bifida-Fact-Sheet|title=Spina Bifida Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke|website=www.ninds.nih.gov|access-date=2019-07-26}}</ref> In a frank tethered cord, the cord is not visible on the outside of the body, but has not fully developed and is anchored to the structures inside the spinal column. Think of a tongue tie, where instead of having a free tongue, there is a thick web that attaches the tongue to the base of the mouth. This is similar to what a tethered cord is like. In some cases, the base of the spinal cord, the conus, is much lower than it should be, and this is how neurosurgeons typically diagnose tethered cord. However, the cord can still be tethered without the conus being below the level of the first lumbar vertebrae - this is referred to as an occult or hidden tethered cord, or a tight filum.<ref name=":4">{{Cite web|url=https://csfinfo.org/videos/physician-lecture-videos/csf-lectures-archive/csf-disorders-klinge/|title=3rd CSF Disorders Symposium: The Occult Tethered Cord Syndrome {{!}} CSF|website=csfinfo.org|access-date=2019-07-26}}</ref>

As with [[craniocervical instability]], there have also been anecdotal reports of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) who were later diagnosed with tethered cord, although no scientific publication on this subject exists.<ref>{{Cite web|url=https://forums.phoenixrising.me/index.php?threads/have-you-ruled-out-chiari-as-a-cause-of-your-cfs.56908/|title=Have you ruled out Chiari as a cause of your CFS|last=|first=|date=|website=Phoenix Rising|archive-url=|archive-date=|url-status=|access-date=}}</ref><ref>{{Cite web|url=https://medium.com/@jenbrea/cci-tethered-cord-series-e1e098b5edf|title=CCI + Tethered cord series|last=Brea|first=Jennifer|date=2019-06-06|website=Medium|language=en|access-date=2019-06-06}}</ref><ref>{{Cite web|url=https://www.mechanicalbasis.org/interviews.html|title=Craniocervical instability, Atlantoaxial Instability, Myalgic Encephalomyelitis, ME, CFS|website=MEchanical Basis|language=en|access-date=2019-06-06}}</ref>

== Onset ==
Some researchers, noting that less severe spinal cord traction may remain asymptomatic in childhood<ref name=":3">{{Cite journal|last=Wilberger|first=James E.|last2=Pang|first2=Dachling|date=1982-07-01|title=Tethered cord syndrome in adults|url=https://thejns.org/view/journals/j-neurosurg/57/1/article-p32.xml|journal=Journal of Neurosurgery|language=en-US|volume=57|issue=1|pages=32–47|doi=10.3171/jns.1982.57.1.0032}}</ref>, hypothesize that the age of symptom onset is related to the amount of cord stretch. Factors in adult onset tethered cord syndrome include: transient stretching of the spine, mechanical constriction/narrowing of the spinal canal, and spinal trauma, all in the presence of an already tightly tethered conus medullaris, such as might occur during natural childbirth or in an automobile accident.<ref name=":3" />

== Signs and Symptoms ==
[[File:Tethered cord symptoms (Part II).jpg|thumb|Chiari Neurological Center’s tethered cord questionnaire (Part I)]][[File:Tethered cord symptoms (Part I).jpg|thumb|Chiari Neurological Center’s tethered cord questionnaire (Part II)]]
Symptoms<ref name=":4" /><ref name=":0">{{Cite journal|last=Wilberger|first=James E.|last2=Pang|first2=Dachling|date=1982-07-01|title=Tethered cord syndrome in adults|url=https://thejns.org/view/journals/j-neurosurg/57/1/article-p32.xml|journal=Journal of Neurosurgery|language=en-US|volume=57|issue=1|pages=32–47|doi=10.3171/jns.1982.57.1.0032}}</ref><ref name=":1">{{Cite web|url=https://www.seattlechildrens.org/conditions/brain-nervous-system-mental-conditions/tethered-spinal-cord/|title=Tethered Spinal Cord|website=Seattle Children’s Hospital|language=en|access-date=2019-06-02}}</ref><ref>{{Cite journal|last=Gupta|first=S. K|last2=Khosla|first2=V. K|last3=Sharma|first3=B. S|last4=Mathuriya|first4=S. N|last5=Pathak|first5=A|last6=Tewari|first6=M. K|date=1999-10-01|title=Tethered cord syndrome in adults|url=http://www.sciencedirect.com/science/article/pii/S0090301999001214|journal=Surgical Neurology|volume=52|issue=4|pages=362–370|doi=10.1016/S0090-3019(99)00121-4|issn=0090-3019}}</ref><ref>{{Cite web|url=https://www.hindawi.com/journals/crior/2015/926185/|title=An Unusual Presentation of Adult Tethered Cord Syndrome Associated with Severe Chest and Upper Back Pain|last=Saita|first=Kazuo|last2=Yamaguchi|first2=Takehiko|date=2015|website=Case Reports in Orthopedics|language=en|access-date=2019-06-02|last3=Chikuda|first3=Hirotaka|last4=Akiyama|first4=Toru|last5=Kanda|first5=Shotaro}}</ref><ref name=":5">{{Cite web|url=https://www.aans.org/|title=Tethered Spinal Cord Syndrome – Causes, Diagnosis and Treatments|website=www.aans.org|language=en|access-date=2019-06-02}}</ref><ref>{{Citation|title=2019 ASAP Conference: Tethered Cord Syndrome, P Klinge, MD, PhD|url=https://www.youtube.com/watch?v=zpSXSMPiMI8|language=en|access-date=2021-08-11}}</ref> of tethered cord syndrome ''may ''include:
* Leg pain (often migratory/traveling), weakness, and/or numbness
* Neck pain
* Suboccipital pain/pressure
* Lower back pain
* Pulling sensation (on brain or upper spine, from below)
* Neck or spine stiffness
* Restless legs
* Rectal pain
* Urinary urgency or incontinence
* Frequent urination (*most people urinate 6-7 times in a 24 hour period)
* Urinary retention / difficulty emptying bladder completely
* Bowel dysfunction
* Constipation
* Numbness under soles of feet
* Falling/tripping/clumsiness
* Decreased sensation or and/or hypersensitivity in feet
* Decreased sensation and/or hypersensitivity in genitals
* Decreased interest in sex
* Difficulty maintaining arousal or achieving orgasm
* Seizure
* Tinnitus
Signs of tethered cord syndrome ''may ''include:
* Sacral dimple (see 10A.2)
* Birthmark, hole in skin, or tuft of hair in lumbar area
* Scoliosis
* Kyphosis
* Hip/knee subluxations
* Sacral pain
* Foot/ankle deformities
* Asymmetry in neurological deficits
* Hyperreflexia/clonus
* Tremors
* Light touch deficit
* Curling toes
Symptoms tend to increase when:
* Walking or running
* Walking on heels
* Walking up stairs
* Laying completely flat
Symptoms tend to decrease when:
* Walking on toes
* Laying with knees bent
* Avoiding walking long distances
* Avoiding standing still
Childhood indictors (relevant for children as well as adults who may have mild and largely assymptomatic prior to illness onset):
* Cutaneous signs at birth, e.g., sacral dimple, birth mark, hole, tuft of hair in lumbar area
* Late bedwetting
* Growing pains
* Walking on toes as a child (and/or prefering high heels or wedge shoes as an adult)
* Difficulty running
* ”Clumsiness”
* Thoracic kyphosis (hunched shoulders) after puberty/with growth in height
* Scoliosis
Other possible indicators:
* Frequent urinary tract infections
* Interstitial cystisis
* Pelvic floor dysfunction

*

== Diagnosis ==

=== Imaging ===
If a tethered cord is suspected, one or more tests may be necessary to confirm the diagnosis. The most common is a lumbar MRI, but a [[myleogram]], CT scan, or ultrasound may also aid in diagnosis<ref>{{Cite web|url=https://www.aans.org/|title=Tethered Spinal Cord Syndrome – Causes, Diagnosis and Treatments|website=www.aans.org|language=en|access-date=2019-07-26}}</ref>

=== '''Occult tethered cord syndrome''' ===
{{Video|id=https://youtu.be/MF0i0CGKkMI|service=youtube|dimensions=550|description=|alignment=right|urlargs=}}Occult tethered cord syndrome describes patients with the signs and symptoms of tethered cord syndrome but who have normal neuroimaging. These cases are often diagnosed via a urodynamics study, which can reveal neurogenic bladder.<ref>{{Cite journal|last=Metcalfe|first=P. D.|last2=Luerssen|first2=T. G.|last3=King|first3=S. J.|last4=Kaefer|first4=M.|last5=Meldrum|first5=K. K.|last6=Cain|first6=M. P.|last7=Rink|first7=R. C.|last8=Casale|first8=A. J.|date=Oct 2006|title=Treatment of the occult tethered spinal cord for neuropathic bladder: results of sectioning the filum terminale|url=https://www.ncbi.nlm.nih.gov/pubmed/16945660|journal=The Journal of Urology|volume=176|issue=4 Pt 2|pages=1826–1829; discussion 1830|doi=10.1016/j.juro.2006.04.090|issn=0022-5347|pmid=16945660}}</ref>

== Treatment ==
There is no standard technique in the surgical treatment of TCS. Generally, the lamina is removed, anywhere from L2 to S1, a durotomy is made, and electrical stimulation is used to confirm the absence of any nerve roots which may be associated with the filum. Finally, a microsurgical resection of the filum terminale (usually a 10 mm segment for pathology) is performed. The filum tends to be taut, and to briskly retract upon sectioning. However, findings are variable, and there is no evidence to suggest that the intraoperative findings predict or correlate with the surgical outcome and severity of the TCS. In some cases, it may be necessary to perform a lumbar stabilization across the motion segment in which the filum was sectioned. The resected filum should be sent for histopathological evaluation.<ref>{{Cite journal|last=Henderson|first=Fraser C.|last2=Austin|first2=Claudiu|last3=Benzel|first3=Edward|last4=Bolognese|first4=Paolo|last5=Ellenbogen|first5=Richard|last6=Francomano|first6=Clair A.|last7=Ireton|first7=Candace|last8=Klinge|first8=Petra|last9=Koby|first9=Myles|date=2017|title=Neurological and spinal manifestations of the Ehlers–Danlos syndromes|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1|pages=195–211|doi=10.1002/ajmg.c.31549|issn=1552-4876}}</ref>
[[File:04804D02-7E65-4543-9BAF-DA3B4CF140D6.jpg|thumb|a: Tethered cord syndrome: conus at the normal level (L1), fatty filum suggestive of tethered cord syndrome (Sagittal view lumbar spine, T1 weighted MRI). b: Tethered cord syndrome: the thickened filum terminale at the L2 level, just before division. (Intraoperative photograph of the lumbar spine thecal sac and the durotomy).]]

== Pathophysiology ==

=== Metabolism ===
Tethered cord, a form of mechanical [[neural strain]], is associated with impaired glucose metabolism in spinal cord tissue,<ref name=":2" /> changes in the reduction/oxidation ratio of [[cytochrome oxidase]].<ref>{{Cite journal|last=Yamada|first=Shoko M.|last2=Won|first2=Daniel J.|last3=Yamada|first3=Shokei|date=2004-02-01|title=Pathophysiology of tethered cord syndrome: correlation with symptomatology|url=https://thejns.org/view/journals/neurosurg-focus/16/2/foc.2004.16.2.7.xml|journal=Neurosurgical Focus|language=en-US|volume=16|issue=2|pages=1–5|doi=10.3171/foc.2004.16.2.7|issn=1092-0684}}</ref> and reduced ATP production.<ref>{{Cite journal|last=Sullivan|first=Stephen|last2=Park|first2=Paul|last3=Stetler|first3=William R.|date=2010-07-01|title=Pathophysiology of adult tethered cord syndrome: review of the literature|url=https://thejns.org/view/journals/neurosurg-focus/29/1/2010.3.focus1080.xml|journal=Neurosurgical Focus|language=en-US|volume=29|issue=1|pages=E2|doi=10.3171/2010.3.FOCUS1080|issn=1092-0684}}</ref> Energy loss due to neural membrane stretching contributes to leakage of [[sodium]], [[potassium]] and [[calcium]].<ref>{{Cite journal|last=Yamada|first=Shokei|last2=Iacono|first2=Robert P.|last3=Andrade|first3=Terry|last4=Mandybur|first4=George|last5=Yamada|first5=Brian S.|date=1995-04-01|title=Pathophysiology of Tethered Cord Syndrome|url=http://www.sciencedirect.com/science/article/pii/S1042368018304650|journal=Neurosurgery Clinics of North America|series=Spinal Dysraphism|volume=6|issue=2|pages=311–323|doi=10.1016/S1042-3680(18)30465-0|issn=1042-3680}}</ref>

A study of energy cost of walking in adolescents with tethered cord, as measured by oxygen uptake, found that “energy cost per metre during walking at preferred speed and physical strain were higher than in peers without disability.”<ref>{{Cite journal|last=Bruinings|first=A. L.|last2=Berg‐Emons|first2=H. J. G. Van Den|last3=Buffart|first3=L. M.|last4=Heijden‐Maessen|first4=H. C. M. Van Der|last5=Roebroeck|first5=M. E.|last6=Stam|first6=H. J.|date=2007|title=Energy cost and physical strain of daily activities in adolescents and young adults with myelomeningocele|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8749.2007.00672.x|journal=Developmental Medicine & Child Neurology|language=en|volume=49|issue=9|pages=672–677|doi=10.1111/j.1469-8749.2007.00672.x|issn=1469-8749}}</ref>

=== Blood flow ===
People with tethered cord syndrome have reduced blood flow to the spinal cord.<ref name=":2" />

“Traction on the caudal cord results in decreased blood flow causing metabolic derangements that culminate in motor, sensory, and urinary neurological deficits. The untethering operation restores blood flow and reverses the clinical picture in most symptomatic cases.”<ref>{{Cite journal|last=Rekate|first=Harold L.|last2=Theodore|first2=Nicholas|last3=Kalani|first3=M. Yashar|last4=Filippidis|first4=Aristotelis S.|date=2010-07-01|title=Spinal cord traction, vascular compromise, hypoxia, and metabolic derangements in the pathophysiology of tethered cord syndrome|url=https://thejns.org/view/journals/neurosurg-focus/29/1/2010.3.focus1085.xml|journal=Neurosurgical Focus|language=en-US|volume=29|issue=1|pages=E9|doi=10.3171/2010.3.FOCUS1085|issn=1092-0684}}</ref>

In a study of five children undergoing surgery for tethered cord syndrome group, spinal cord blood flow prior to untethering was a mean of 12.6 ml/min per 100 g of tissue. It increased in all cases after release to a mean of 29.4 ml/min per 100 g of tissue.<ref>{{Cite journal|last=Danto|first=Joseph|last2=Greenberg|first2=Burt M.|last3=Rosenthal|first3=Alan D.|last4=Schneider|first4=Steven J.|date=1993-02-01|title=A Preliminary Report on the Use of Laser-Doppler Flowmetry during Tethered Spinal Cord Release|url=https://academic.oup.com/neurosurgery/article/32/2/214/2804055|journal=Neurosurgery|language=en|volume=32|issue=2|pages=214–218|doi=10.1227/00006123-199302000-00010|issn=0148-396X}}</ref>

== Co-morbidities ==
* [[Ehlers-Danlos syndrome]]
* [[Craniocervical instability]]
* [[Fibromyalgia]]<ref>{{Cite journal|last=Mantia|first=Roberto|last2=Di Gesù|first2=Marco|last3=Vetro|first3=Angelo|last4=Mantia|first4=Fabrizio|last5=Palma|first5=Sebastiano|last6=Iovane|first6=Angelo|date=2015-03-27|title=Shortness of filum terminale represents an anatomical specific feature in fibromyalgia: a nuclear magnetic resonance and clinical study|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396674/|journal=Muscles, Ligaments and Tendons Journal|volume=5|issue=1|pages=33–37|issn=2240-4554|pmc=4396674|pmid=25878985}}</ref>

== See also ==
* [[Craniocervical instability]]

== Learn more ==

* “[https://thejns.org/spine/view/journals/j-neurosurg-spine/10/1/article-p79.xml Tethered Cord Syndrome],” ''Journal of Neurosurgery'', ''2009.''

== References ==
{{reflist}}
[[Category:Neurology]]
[[Category:Diagnoses]]
[[Category:Neurological diseases and disorders]]

Cardiopulmonary exercise test

2021-08-11T18:04:31Z

JenB:/* Long COVID */

Cardiopulmonary exercise testing (CPET or CPEX), also referred to as a VO2 (oxygen consumption) test, is a '''specialized type of stress test or exercise test''' that measures your exercise ability. It has been used extensively to study [[Myalgic encephalomyelitis]]/[[Chronic fatigue syndrome]] and is considered a [[Diagnostic biomarker|potential biomarker]] for the syndrome.

== ME/CFS ==
{{Main article|page_name=Two-day cardiopulmonary exercise test}}

== Long COVID ==
In a single CPET test, [[Long COVID|Post-COVID-19]] patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.<ref>{{Cite journal|last=Singh|first=Inderjit|last2=Joseph|first2=Phillip|last3=Heerdt|first3=Paul M.|last4=Cullinan|first4=Marjorie|last5=Lutchmansingh|first5=Denyse D.|last6=Gulati|first6=Mridu|last7=Possick|first7=Jennifer D.|last8=Systrom|first8=David M.|last9=Waxman|first9=Aaron B.|date=2021-08-10|title=Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.|url=https://journal.chestnet.org/article/S0012-3692(21)03635-7/abstract|journal=CHEST|language=English|volume=0|issue=0|doi=10.1016/j.chest.2021.08.010|issn=0012-3692}}</ref>

== See also ==
* [[Two-day cardiopulmonary exercise test]]

== References ==
<references />

CPET

2021-08-11T18:00:13Z

JenB:Redirected page to Cardiopulmonary exercise test

#REDIRECT [[Cardiopulmonary exercise test]]
[[Category:Tests]]
[[Category:Medical tests]]

Cardiopulmonary exercise test

2021-08-11T17:59:10Z

JenB:

Cardiopulmonary exercise testing (CPET or CPEX), also referred to as a VO2 (oxygen consumption) test, is a '''specialized type of stress test or exercise test''' that measures your exercise ability. It has been used extensively to study [[Myalgic encephalomyelitis]]/[[Chronic fatigue syndrome]] and is considered a [[Diagnostic biomarker|potential biomarker]] for the syndrome.

== ME/CFS ==
{{Main article|page_name=Two-day cardiopulmonary exercise test}}

== Long COVID ==
In a single CPET test, Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.<ref>{{Cite journal|last=Singh|first=Inderjit|last2=Joseph|first2=Phillip|last3=Heerdt|first3=Paul M.|last4=Cullinan|first4=Marjorie|last5=Lutchmansingh|first5=Denyse D.|last6=Gulati|first6=Mridu|last7=Possick|first7=Jennifer D.|last8=Systrom|first8=David M.|last9=Waxman|first9=Aaron B.|date=2021-08-10|title=Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.|url=https://journal.chestnet.org/article/S0012-3692(21)03635-7/abstract|journal=CHEST|language=English|volume=0|issue=0|doi=10.1016/j.chest.2021.08.010|issn=0012-3692}}</ref>

== See also ==
* [[Two-day cardiopulmonary exercise test]]

== References ==

Long COVID pathophysiology

2021-08-11T17:46:39Z

JenB:Edited CPET study

'''[[Long COVID]]''', '''long tail covid''', '''Post-Acute Sequelae of COVID-19''' '''(PASC)''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.

== Overview ==
{{Main article|page_name=Long COVID}}

== Pathophysiology ==

=== Infection and immunity ===
A range of [[Antibody|antibodies]] have been found in patients with persistent post-acute COVID symptoms. Elevated [[G-protein coupled receptor]] autoantibodies have been found.<ref>{{Cite journal|date=2021-01-01|title=Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms|url=https://www.sciencedirect.com/science/article/pii/S2589909021000204|journal=Journal of Translational Autoimmunity|language=en|volume=4|pages=100100|doi=10.1016/j.jtauto.2021.100100|issn=2589-9090}}</ref> One study founded elevated [[antinuclear antibody]] (ANA) titles in 43.6% of long COVID patients twelve months after symptom onset.<ref>{{Cite journal|last=Seeßle|first=Jessica|last2=Waterboer|first2=Tim|last3=Hippchen|first3=Theresa|last4=Simon|first4=Julia|last5=Kirchner|first5=Marietta|last6=Lim|first6=Adeline|last7=Müller|first7=Barbara|last8=Merle|first8=Uta|date=2021-07-05|title=Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study|url=https://doi.org/10.1093/cid/ciab611|journal=Clinical Infectious Diseases|issue=ciab611|doi=10.1093/cid/ciab611|issn=1058-4838}}</ref>

Long COVID may be associated [[herpesvirus]] reactivation such as [[Epstein-Barr virus|Epstein-Barr Virus]],<ref>{{Cite journal|last=Gold|first=Jeffrey E.|last2=Okyay|first2=Ramazan A.|last3=Licht|first3=Warren E.|last4=Hurley|first4=David J.|date=2021/6|title=Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation|url=https://www.mdpi.com/2076-0817/10/6/763|journal=Pathogens|language=en|volume=10|issue=6|pages=763|doi=10.3390/pathogens10060763}}</ref> which has been shown to cause elevations of certain G-protein coupled receptor autoantibody types.<ref>{{cite book|last1=Angelini|first1=Lucia|last2=Bardare|first2=Maria|last3=Martini|first3=Alberto|year=2002|title=Immune-mediated Disorders of the Central Nervous System in Children|url=https://books.google.com/books?id=5trQOK8hcZUC&pg=PA7&lpg=PA7&dq=coxsackie+b+acetylcholine&source=bl&ots=zhup8ZXq68&sig=CxDwQCHO8-OMBYkcp4EayjnDKnw&hl=en&sa=X&ved=0ahUKEwjflpmqg9fOAhWBeSYKHSR4Dh0Q6AEIMTAD#v=onepage&q=coxsackie%20b%20acetylcholine&f=false}}</ref><ref>{{Cite journal|last=Gebhardt|first=B. M.|date=2000-06-26|title=Evidence for antigenic cross-reactivity between herpesvirus and the acetylcholine receptor|url=http://www.ncbi.nlm.nih.gov/pubmed/10742556|journal=Journal of Neuroimmunology|volume=105|issue=2|pages=145–153|issn=0165-5728|pmid=10742556}}</ref><ref>{{Cite journal|last=Brenner|first=T.|last2=Timore|first2=Y.|last3=Wirguin|first3=I.|last4=Abramsky|first4=O.|last5=Steinitz|first5=M.|date=Oct 1989|title=In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis|url=http://www.ncbi.nlm.nih.gov/pubmed/2553772|journal=Journal of Neuroimmunology|volume=24|issue=3|pages=217–222|issn=0165-5728|pmid=2553772}}</ref><ref>{{Cite journal|last=Kaminski|first=Henry J.|last2=Janos|first2=Minarovits|title=Epstein-barr virus: Trigger for autoimmunity?|url=http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/|journal=Annals of Neurology|language=en|issn=0364-5134}}</ref><ref>{{Cite web|url=http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10|title=Official Brain & Life Home Page|website=journals.lww.com|language=en|access-date=2018-08-10}}</ref>

=== Neurological and neuropsychiatric ===

=== Cardiovascular ===

=== Pulmonary ===
In a single [[cardiopulmonary exercise test]], Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.<ref>{{Cite journal|last=Singh|first=Inderjit|last2=Joseph|first2=Phillip|last3=Heerdt|first3=Paul M.|last4=Cullinan|first4=Marjorie|last5=Lutchmansingh|first5=Denyse D.|last6=Gulati|first6=Mridu|last7=Possick|first7=Jennifer D.|last8=Systrom|first8=David M.|last9=Waxman|first9=Aaron B.|date=2021-08-10|title=Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.|url=https://journal.chestnet.org/article/S0012-3692(21)03635-7/abstract|journal=CHEST|language=English|volume=0|issue=0|doi=10.1016/j.chest.2021.08.010|issn=0012-3692}}</ref>

== Comparison to other conditions ==

=== Post-acute SARS ===

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

=== POTS ===
{{Main|page_name=Postural orthostatic tachycardia syndrome}}

=== MCAS ===
{{Main|page_name=Mast cell activation syndrome}}

=== Alzheimer’s ===

=== Traumatic Brain Injury ===
{| class="wikitable"
!Findings
!Long COVID
!Post-acute SARS
!ME/CFS
!POTS
!MCAS
|-
|G-protein coupled receptor autoantibodies
|β2- and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, nociceptin- and ETA-receptors
|
|M3 and M4 [[Muscarinic acetylcholine receptor|muscarinic acetylcholine receptors]], as well as ß2 [[Adrenergic receptor|adrenergic receptors]]
|α1, β1 and β2 adrenergic receptor autoantibodies
|
|-
|
|
|
|
|
|
|-
|
|
|
|
|
|
|}

== See also ==
* [[Long COVID]]

== Learn more ==
* [https://docs.google.com/spreadsheets/d/1gF-kMUxJWNrwxbmoMW2wGKTMlksRUAROjh7b97G9IE8/edit Long COVID Resource Hub] (database of Long COVID research)

== References ==
<references />

Long COVID pathophysiology

2021-08-11T17:46:07Z

JenB:Added CPET study

'''[[Long COVID]]''', '''long tail covid''', '''Post-Acute Sequelae of COVID-19''' '''(PASC)''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.

== Overview ==
{{Main article|page_name=Long COVID}}

== Pathophysiology ==

=== Infection and immunity ===
A range of [[Antibody|antibodies]] have been found in patients with persistent post-acute COVID symptoms. Elevated [[G-protein coupled receptor]] autoantibodies have been found.<ref>{{Cite journal|date=2021-01-01|title=Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms|url=https://www.sciencedirect.com/science/article/pii/S2589909021000204|journal=Journal of Translational Autoimmunity|language=en|volume=4|pages=100100|doi=10.1016/j.jtauto.2021.100100|issn=2589-9090}}</ref> One study founded elevated [[antinuclear antibody]] (ANA) titles in 43.6% of long COVID patients twelve months after symptom onset.<ref>{{Cite journal|last=Seeßle|first=Jessica|last2=Waterboer|first2=Tim|last3=Hippchen|first3=Theresa|last4=Simon|first4=Julia|last5=Kirchner|first5=Marietta|last6=Lim|first6=Adeline|last7=Müller|first7=Barbara|last8=Merle|first8=Uta|date=2021-07-05|title=Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study|url=https://doi.org/10.1093/cid/ciab611|journal=Clinical Infectious Diseases|issue=ciab611|doi=10.1093/cid/ciab611|issn=1058-4838}}</ref>

Long COVID may be associated [[herpesvirus]] reactivation such as [[Epstein-Barr virus|Epstein-Barr Virus]],<ref>{{Cite journal|last=Gold|first=Jeffrey E.|last2=Okyay|first2=Ramazan A.|last3=Licht|first3=Warren E.|last4=Hurley|first4=David J.|date=2021/6|title=Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation|url=https://www.mdpi.com/2076-0817/10/6/763|journal=Pathogens|language=en|volume=10|issue=6|pages=763|doi=10.3390/pathogens10060763}}</ref> which has been shown to cause elevations of certain G-protein coupled receptor autoantibody types.<ref>{{cite book|last1=Angelini|first1=Lucia|last2=Bardare|first2=Maria|last3=Martini|first3=Alberto|year=2002|title=Immune-mediated Disorders of the Central Nervous System in Children|url=https://books.google.com/books?id=5trQOK8hcZUC&pg=PA7&lpg=PA7&dq=coxsackie+b+acetylcholine&source=bl&ots=zhup8ZXq68&sig=CxDwQCHO8-OMBYkcp4EayjnDKnw&hl=en&sa=X&ved=0ahUKEwjflpmqg9fOAhWBeSYKHSR4Dh0Q6AEIMTAD#v=onepage&q=coxsackie%20b%20acetylcholine&f=false}}</ref><ref>{{Cite journal|last=Gebhardt|first=B. M.|date=2000-06-26|title=Evidence for antigenic cross-reactivity between herpesvirus and the acetylcholine receptor|url=http://www.ncbi.nlm.nih.gov/pubmed/10742556|journal=Journal of Neuroimmunology|volume=105|issue=2|pages=145–153|issn=0165-5728|pmid=10742556}}</ref><ref>{{Cite journal|last=Brenner|first=T.|last2=Timore|first2=Y.|last3=Wirguin|first3=I.|last4=Abramsky|first4=O.|last5=Steinitz|first5=M.|date=Oct 1989|title=In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis|url=http://www.ncbi.nlm.nih.gov/pubmed/2553772|journal=Journal of Neuroimmunology|volume=24|issue=3|pages=217–222|issn=0165-5728|pmid=2553772}}</ref><ref>{{Cite journal|last=Kaminski|first=Henry J.|last2=Janos|first2=Minarovits|title=Epstein-barr virus: Trigger for autoimmunity?|url=http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/|journal=Annals of Neurology|language=en|issn=0364-5134}}</ref><ref>{{Cite web|url=http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10|title=Official Brain & Life Home Page|website=journals.lww.com|language=en|access-date=2018-08-10}}</ref>

=== Neurological and neuropsychiatric ===

=== Cardiovascular ===

=== Pulmonary ===
In a single CPET test, Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.<ref>{{Cite journal|last=Singh|first=Inderjit|last2=Joseph|first2=Phillip|last3=Heerdt|first3=Paul M.|last4=Cullinan|first4=Marjorie|last5=Lutchmansingh|first5=Denyse D.|last6=Gulati|first6=Mridu|last7=Possick|first7=Jennifer D.|last8=Systrom|first8=David M.|last9=Waxman|first9=Aaron B.|date=2021-08-10|title=Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.|url=https://journal.chestnet.org/article/S0012-3692(21)03635-7/abstract|journal=CHEST|language=English|volume=0|issue=0|doi=10.1016/j.chest.2021.08.010|issn=0012-3692}}</ref>

== Comparison to other conditions ==

=== Post-acute SARS ===

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

=== POTS ===
{{Main|page_name=Postural orthostatic tachycardia syndrome}}

=== MCAS ===
{{Main|page_name=Mast cell activation syndrome}}

=== Alzheimer’s ===

=== Traumatic Brain Injury ===
{| class="wikitable"
!Findings
!Long COVID
!Post-acute SARS
!ME/CFS
!POTS
!MCAS
|-
|G-protein coupled receptor autoantibodies
|β2- and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, nociceptin- and ETA-receptors
|
|M3 and M4 [[Muscarinic acetylcholine receptor|muscarinic acetylcholine receptors]], as well as ß2 [[Adrenergic receptor|adrenergic receptors]]
|α1, β1 and β2 adrenergic receptor autoantibodies
|
|-
|
|
|
|
|
|
|-
|
|
|
|
|
|
|}

== See also ==
* [[Long COVID]]

== Learn more ==
* [https://docs.google.com/spreadsheets/d/1gF-kMUxJWNrwxbmoMW2wGKTMlksRUAROjh7b97G9IE8/edit Long COVID Resource Hub] (database of Long COVID research)

== References ==
<references />

Cardiopulmonary exercise test

2021-08-11T17:40:25Z

JenB:Created as independent page

See also

[[Two-day cardiopulmonary exercise test]]

Two-day cardiopulmonary exercise test

2021-08-11T17:39:43Z

JenB:

'''Two-day cardiopulmonary exercise test or 2-day CPET''' is a procedure which assesses exercise capacity and recovery by performing two exercise tests 24 hours apart.<ref name=":2">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|date=2018|title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/30234078|journal=Frontiers in Pediatrics|volume=6|pages=242|doi=10.3389/fped.2018.00242|issn=2296-2360|pmc=6131594|pmid=30234078}}</ref> The hypothesis is that ME/CFS patients display a characteristic deterioration in exercise capacity on the second test, a finding that has been reported by multiple research groups.<ref name=":1" /><ref name=":3" /><ref name=":0" />[[File:CPET.jpg|alt=Photo of a woman walking on a treadmill while wearing a clear mask over her nose and mouth, and attached to a cart holding medical equipment.|thumb|350x350px|Cardiopulmonary Exercise Test]]The maximal, symptom-limited [[cardiopulmonary exercise test]] (CPET) is considered the gold standard for measuring physical capacity.<ref>{{Cite journal|last=Chandra|first=Divay|author-link=|last2=Wise|first2=Robert A.|author-link2=|last3=Kulkarni|first3=Hrishikesh S.|author-link3=|last4=Benzo|first4=Roberto P.|author-link4=|last5=Criner|first5=Gerard|author-link5=|last6=Make|first6=Barry|author-link6=|last7=Slivka|first7=William A.|last8=Ries|first8=Andrew L.|last9=Reilly|first9=John J.|date=Dec 2012|title=Optimizing the 6-Min Walk Test as a Measure of Exercise Capacity in COPD|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515028/|journal=Chest|volume=142|issue=6|pages=1545–1552|doi=10.1378/chest.11-2702|issn=0012-3692|pmc=3515028|pmid=23364913|quote=|via=}}</ref><ref>{{Cite journal|last=Demir|first=Rengin|author-link=|last2=Küçükoğlu|first2=Mehmet Serdar|author-link2=|author-link3=|author-link4=|author-link5=|author-link6=|date=Dec 2010|title=Evaluation of exercise capacity in pulmonary arterial hypertension|url=https://www.ncbi.nlm.nih.gov/m/pubmed/21248462/|journal=Turk Kardiyoloji Dernegi Arsivi: Turk Kardiyoloji Derneginin Yayin Organidir|volume=38|issue=8|pages=580–588|issn=1016-5169|pmid=21248462|quote=|via=}}</ref> This test measures gas exchange parameters using a mouthpiece or mask, while participants exercise on a treadmill or stationary bicycle with a controlled increase in resistance or power output. It is commonly used to measure the fitness level of athletes, as well as patients with cardiopulmonary disease.<ref>{{Cite journal|last=Albouaini|first=Khaled|last2=Egred|first2=Mohaned|last3=Alahmar|first3=Albert|last4=Wright|first4=David Justin|date=Nov 2007|title=Cardiopulmonary exercise testing and its application|url=https://www.ncbi.nlm.nih.gov/pubmed/17989266|journal=Postgraduate Medical Journal|volume=83|issue=985|pages=675–682|doi=10.1136/hrt.2007.121558|issn=1469-0756|pmc=2734442|pmid=17989266}}</ref> In these populations, CPET measures are highly reliable and reproducible.<ref name=":2" /> Exercise physiologists however have noted that ME/CFS patients are unable to reproduce these measurements on consecutive days, despite meeting criteria for maximal effort.<ref name=":4" /> According to a 2015 report by The National Academy of Medicine, “ME/CFS patients have significantly lower results on CPET 2 than on CPET 1 on one or more of the following parameters: VO2max, VO2 at ventilatory threshold and maximal workload or workload at ventilatory threshold.”<ref name=":5">{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK274235/|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|last=Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|last2=Board on the Health of Select Populations|last3=Institute of Medicine|date=2015|publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref>

Specifically, VO2Max is the true maximal oxygen consumption of a participant, VO2Peak is the recorded maximal oxygen consumption of a participant and VO2 at ventilatory threshold is the oxygen consumption at the first key threshold (VT or VT1), otherwise known as the gas exchange threshold (GET). This threshold is the point at which carbon dioxide output (VCO2) and oxygen consumption no longer increase linearly, which occurs at 40-75% of VO2Max, depending on the fitness and health of the participants. The VT1 is commonly determined using the V-slope method, which notes the point of non linearity when VO2 is plotted against VCO2. The VT1 can also be indicated using the ventilatory equivalent method, plotting VE/VO2 and VE/VCO2 on the same graph and noting the point where VE/VO2 increases significantly, while VE/VCO2 remains flat (where VE is minute ventilation, which is the total amount of gas inhaled or exhaled from the lungs per minute). While the VT1 is primarily determined by peripheral metabolic factors, it is not synonymous with the lactate threshold which is the point at which lactate starts to accumulate significantly in the blood. The lactate threshold is not only dependent on lactate/pyruvate equilibrium inside the muscle cells, but the kinetics of lactate transport into and out of cells. Nor is VT1 synonymous with the onset of acidosis which is additionally affected by pH buffering within the cell and the circulatory system. It is also important to point out that this gas exchange threshold is not caused by shortness of breath, nor hyperventilation, since neither hypocapnia nor hypercapnia occur at this threshold. There is however, a second ventilatory threshold (VT2) otherwise known as the respiratory compensation point (RCP), and typically occurs at 85-90% of VO2Max. This respiratory compensation occurs when a significant reduction in blood or cerebrospinal fluid pH activates chemoreceptors, which stimulate the respiratory centre of the brain, leading to compensatory hyperventilation to help restore the pH balance.

According to researchers in the field, the abnormal results of ME/CFS patients on the 2-day CPET reflect post-exertional malaise (PEM), a marked symptom exacerbation after exercise thought to be characteristic of this condition.<ref name=":1" /> The 2015 report by National Academy of medicine indicated that the 2-day CPET protocol can be used as an objective indicator that physical exertion decreases subsequent function in patients with ME/CFS, for example in obtaining social security disability.<ref name=":5" /> The 2-day CPET protocol however is not required in making the diagnosis of ME/CFS. Some have expressed concern that exercise tests may significantly worsen the condition of ME/CFS patients.<ref name=":5" /><ref>{{Cite journal|last=Nijs|first=J.|last2=Van Oosterwijck|first2=J.|last3=Meeus|first3=M.|last4=Lambrecht|first4=L.|last5=Metzger|first5=K.|last6=Frémont|first6=M.|last7=Paul|first7=L.|date=Apr 2010|title=Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta|url=https://www.ncbi.nlm.nih.gov/pubmed/20433584|journal=Journal of Internal Medicine|volume=267|issue=4|pages=418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=1365-2796|pmid=20433584}}</ref><ref>{{Cite journal|last=VanNess|first=J. Mark|last2=Stevens|first2=Staci R.|last3=Bateman|first3=Lucinda|last4=Stiles|first4=Travis L.|last5=Snell|first5=Christopher R.|date=Feb 2010|title=Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health (2002)|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref><ref name=":0" />

==Evidence==
[[Mark VanNess]], [[Christopher Snell]] and [[Staci Stevens]] of the University of the Pacific, Stockton, CA, were the first to study the two-day CPET procedure in patients with ME/CFS. In a 2007 study published in the [[Journal of Chronic Fatigue Syndrome]], they compared six ME/CFS patients with six controls. At the first CPET there were no major differences between the two groups. At the second CPET however, ME/CFS patients reached significantly lower peak [[oxygen]] consumption (VO2Peak) and oxygen consumption at aerobic threshold.<ref name=":4">{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref>

In 2010, a Dutch research group including Ruud Vermeulen and [[Frans Visser]] used the 2-day CPET in a study with 15 female ME/CFS and 15 healthy controls. Patients reached the aerobic threshold and the maximal exercise at much lower oxygen consumption than controls, an effect that was magnified during the second-day exercise test. Since levels of creatine kinase in the blood and oxidative phosphorylation in mononuclear cells were normal in patients before and after exercise, Vermeulen et al. speculated that the lowered anaerobic threshold was not so much a result of [[mitochondrion|mitochondrial]] insufficiency, but of impaired oxygen transport to the [[Muscle|muscles]].<ref>{{Cite journal|last=Vermeulen|first=Ruud C. W.|last2=Kurk|first2=Ruud M.|last3=Visser|first3=Frans C.|last4=Sluiter|first4=Wim|last5=Scholte|first5=Hans R.|date=2010-10-11|title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=https://www.ncbi.nlm.nih.gov/pubmed/20937116|journal=Journal of Translational Medicine|volume=8|pages=93|doi=10.1186/1479-5876-8-93|issn=1479-5876|pmc=2964609|pmid=20937116}}</ref>

In 2013, [[Christopher Snell|Snell]], [[Staci Stevens|Stevens]] and [[Mark VanNess|VanNess]] tested the 2-day CPET procedure in a larger sample of 51 ME/CFS patients and 10 healthy controls. Once again, there were no sufficient differences between the groups at the first CPET. During the exercise test on the second day however, ME/CFS patients showed much lower oxygen consumption and workload at peak exercise and at aerobic threshold. Group differences were not due to lack of effort since most participants attained the ventilatory threshold and achieved a respiratory exchange ratio of greater than or equal to 1.1.<ref name=":0">{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|language=en|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref>

In 2014, the research group of [[Betsy Keller]] used the 2-day CPET protocol in a study involving 22 ME/CVS patient. A decline on several physiological measures was found (see table), while the respiratory exchange ratio indicated maximum efforts by participants during both exercise tests.<ref name=":1">{{Cite journal|last=Keller|first=Betsy A.|last2=Pryor|first2=John Luke|last3=Giloteaux|first3=Ludovic|date=2014-04-23|title=Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref>

This group followed this research up with a study of a single pair of monozygotic twins in 2016.<ref>{{Cite journal|title=A Pair of Identical Twins Discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Differ in Physiological Parameters and Gut Microbiome Composition|url=http://www.amjcaserep.com/abstract/index/idArt/900314|journal=American Journal of Case Reports|date=2016-10-10|issn=1941-5923|pmc = 5058431|pmid=27721367|pages=720–729|volume=17|doi=10.12659/AJCR.900314|language=en|first=Ludovic|last=Giloteaux|first2=Maureen R.|last2=Hanson|first3=Betsy A.|last3=Keller}}</ref>
{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS (bold indicates statistical significance)
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|VanNess et al. 2007.
|6
|'''-22%'''
|'''-26%'''
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.
|15
|'''-6.3%'''
|'''-7.0%'''
|'''-5.3%'''
|'''-7.0%'''
|<nowiki>-1.9%</nowiki>
|'''-8.8%'''
|-
|Snell et al. 2013.
|51
| -5%
|'''-10.8%'''
|'''-7.2%'''
|'''-55.2%'''
|?
|?
|-
|Keller et al. 2014.
|22
|'''-13.8%'''
|'''-15.8%'''
|'''-12.5%'''
|'''-21.3%'''
|'''-5.9%'''
|'''-12.6%'''
|-
|Giloteaux et al. 2016.
|1 (monozygotic twin)
|0%
| -13.4%
|0%
| -25%
| +7.4%
| -19% (calculated)
|-
|Hodges et al. 2017.
|10
|<nowiki>+5.3%</nowiki>
|<nowiki>+6.1%</nowiki>
|<nowiki>-6.7%</nowiki>
|'''-11.4%'''
|<nowiki>-0.6%</nowiki>
| +7% (calculated)
|-
|Nelson et al. 2019.
|16
| +0.4%
| -3.1%
| -1.2%
|'''-17.4%'''
| -0.5%
| +2% (calculated)
|-
|Lien et al. 2019. (numerical estimates)

|18
| -5%
| -6%
| -2%
|'''-7%'''
| +1.5%
|?
|-
|van Campen 2020.A (males)
|25
|'''-10%'''
|'''-22%'''
|'''-10%'''
|'''-30%'''
|'''-5%'''
| -16% (calculated)
|-
|van Campen 2020.B (females)
|31 ("mild" cases)
|'''-6%'''
|'''-21%'''
|'''-10%'''
|'''-26%'''
| -3%
|?
|-
|van Campen 2020.B (females)
|31 ("moderate" cases)
|'''-11%'''
|'''-21%'''
|'''-16%'''
|'''-31%'''
| -6%
|?
|-
|van Campen 2020.B (females)
|20 ("severe" cases)
|'''-12%'''
|'''-19%'''
|'''-19%'''
|'''-33%'''
| -7%
|?
|-
|Davenport 2020.
|51
| -5%
| -10%
| -9%
|'''-11%'''
| -3%
| -7% (calculated)
|-
|van Campen 2021. (males)
|25
|'''-12%'''
|'''-27%'''
|'''-10%'''
|'''-27%'''
| -7%
| -17% (calculated)
|-
|van Campen 2021. (females)
|50
|'''-10%'''
|'''-23%'''
|'''-11%'''
|'''-30%'''
| -4%
| -15% (calculated)
|}
In 2017, a research team form [[New Zealand]] compared the physiological responses during a 2-day CPET, in ten patients with ME/CFS, seven patients with [[Multiple sclerosis|Multiple Sclerosis]] (MS) and seventeen healthy controls. Curiously peak oxygen increased at the second exercise test in ME/CFS patients, but there was a significant reduction noticeable in workload at aerobic threshold, a decline that was not seen in MS-patients or healthy controls. According to the authors: <blockquote>“differences between MS and CFS/ME responses only became evident after a second maximal exercise test, thus suggesting that a repeated protocol is required to not only distinguish CFS/ME from HC, but also from other fatigue-related conditions, who may not suffer from post-exertional malaise and have a differing delayed fatigue profile.”<ref name=":3">{{Cite journal|last=Hodges|first=L. D.|last2=Nielsen|first2=T.|last3=Baken|first3=D.|date=Jul 2018|title=Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4|pages=639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref></blockquote>In 2019 the 2-day CPET procedure was tested by an Australian research team of Nelson and colleagues. They found a significant larger reduction in workload at the ventilatory threshold in patients with ME/CFS compared to healthy controls. A percentage change of −6.3% to −9.8% provided good sensitivity and specificity, indicating this test has the potential to become a biomarker for ME/CFS. However, the sample size of this study was small (16 ME/CFS patients), the control group consisted only of healthy persons (instead of patients with other chronic illnesses) and no significant difference was found in VO2 at the ventilatory threshold.<ref>{{Cite journal|last=Nelson|first=Maximillian J.|last2=Buckley|first2=Jonathan D.|last3=Thomson|first3=Rebecca L.|last4=Clark|first4=Daniel|last5=Kwiatek|first5=Richard|last6=Davison|first6=Kade|date=2019-03-14|title=Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://doi.org/10.1186/s12967-019-1836-0|journal=Journal of Translational Medicine|volume=17|issue=1|pages=80|doi=10.1186/s12967-019-1836-0|issn=1479-5876|pmc = 6417168|pmid=30871578}}</ref>

A Norwegian study published in 2019 also reported a significant larger reduction in workload at the ventilatory threshold in 18 patients with ME/CFS compared to healthy controls, although this was not the case for peak values or VO2 measurement at the ventilatory threshold. The authors also measured arterial lactate concentrations, every 30 seconds during the exercise tests. Lactate was higher per power output per kg in patients than controls and the differences increased significantly at the second exercise test. In the healthy controls lactate concentration at the ventilatory threshold decreased while this was not the case in ME/CFS patients, suggesting a problem in lactate clearance ability.<ref>{{Cite journal|last=Lien|first=Katarina|last2=Johansen|first2=Bjørn|last3=Veierød|first3=Marit B.|last4=Haslestad|first4=Annicke S.|last5=Bøhn|first5=Siv K.|last6=Melsom|first6=Morten N.|last7=Kardel|first7=Kristin R.|last8=Iversen|first8=Per O.|date=2019|title=Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://physoc.onlinelibrary.wiley.com/doi/abs/10.14814/phy2.14138|journal=Physiological Reports|language=en|volume=7|issue=11|pages=e14138|doi=10.14814/phy2.14138|issn=2051-817X}}</ref>

Researchers from the Workwell Foundation published in 2019, a case series of six women, who underwent the 2-day CPET. This study compared two healthy participants, one active, the other sedentary, two ME/CFS patients, one high functioning with high VO2peak, another with low VO2Peak, with a patient suffering from [[HIV/AIDS|human immunodeficiency virus]] (HIV) and another suffering from [[Multiple sclerosis|MS]].<ref>{{Cite journal|last=Larson|first=Benjamin|last2=Davenport|first2=Todd E.|last3=Stevens|first3=Staci R.|last4=Stevens|first4=Jared|last5=Van Ness|first5=J. Mark|last6=Snell|first6=Christopher R.|date=Oct 2019|title=Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions: A Case Series|url=http://insights.ovid.com/crossref?an=01823246-201910000-00004|journal=Cardiopulmonary Physical Therapy Journal|language=en|volume=30|issue=4|pages=145–152|doi=10.1097/CPT.0000000000000100|issn=1541-7891|pmc=|pmid=|quote=|last7=|first7=|last8=|first8=|author-link=|author-link2=Todd Davenport|access-date=|author-link3=Staci Stevens|author-link4=|author-link5=Mark VanNess|author-link6=Christopher Snell|via=}}</ref> The healthy participants and the MS patient reproduced or improved their exercise parameters, namely VO2, workload, heart-rate and minute ventilation at both the ventilatory threshold and peak exercise. The HIV patient reproduced all of these findings except peak workload and peak minute ventilation. The ME/CFS patients were unable to reproduce VO2, workload, heart rate or minute ventilation at the ventilatory threshold. These results continue to suggest that the inability to reproduce workload at the ventilatory threshold is specific to ME/CFS patients, but patients with other fatiguing conditions will need to be tested to confirm this. This study was followed up in 2020 with 51 patients and 10 controls, focusing on additional statistical analysis and discussing the meaning of test-retest reliability in the context of ME/CFS. The main positive finding was a significant group*test (difference) in work rate at the ventilatory threshold. <ref>{{Cite journal|last=Davenport|first=Todd E.|last2=Stevens|first2=Staci R.|last3=Stevens|first3=M. A. Jared|last4=Snell|first4=Christopher R.|last5=Van Ness|first5=J. Mark|date=2020-06-16|title=Properties of measurements obtained during cardiopulmonary exercise testing in individuals with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/WOR-203170|journal=Work|pages=1–10|doi=10.3233/WOR-203170}}</ref>

In 2020, researchers from Stichting Cardio Zorg, a cardiology clinic in the Netherlands published two studies of clinical 2-day CPET results for ME/CFS patients with exercise intolerance. The first study consisted of male patients, to see whether the results from previous studies which had predominantly female patients would be replicated.<ref>{{Cite journal|last=van Campen|first=C. (Linda) M. C.|last2=Rowe|first2=Peter C.|last3=Visser|first3=Frans C.|date=2020|title=Validity of 2-Day Cardiopulmonary Exercise Testing in Male Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.scirp.org/journal/doi.aspx?doi=10.4236/ape.2020.101007|journal=Advances in Physical Education|volume=10|issue=01|pages=68–80|doi=10.4236/ape.2020.101007|issn=2164-0386}}</ref> A second study focused on female patients with differing severity, which were subgrouped according to: “Symptom severity impact must result in a 50% or greater reduction in a patient’s premorbid activity level for a diagnosis of ME. Mild: approximately 50% reduction in activity, moderate: mostly housebound, severe: mostly bedbound and very severe: bedbound and dependent on help for physical functions”.<ref>{{Cite journal|last=van Campen|first=C (Linda) MC|last2=Rowe|first2=Peter C.|last3=Visser|first3=Frans C.|date=2020-06-30|title=Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease|url=https://www.mdpi.com/2227-9032/8/3/192|journal=Healthcare|language=en|volume=8|issue=3|pages=192|doi=10.3390/healthcare8030192|issn=2227-9032}}</ref> This research was followed up in 2021 with a retrospective clinical comparison between 26 male idiopathic chronic fatigue (ICF) cases who did not suffer from PEM and 25 male ME/CFS patients who satisfied the 2011 ME International Consensus Criteria and the 1994 Center for Disease Control criteria for CFS. <ref name=":6">{{Cite journal|last=van Campen|first=C. (Linda) M. C.|last2=Visser|first2=Frans C.|date=Jun 2021|title=Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol|url=https://www.mdpi.com/2227-9032/9/6/683|journal=Healthcare|language=en|volume=9|issue=6|pages=683|doi=10.3390/healthcare9060683|pmc=|pmid=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=Linda van Campen|author-link2=Frans Visser|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> Notably, most ME/CFS patients had a decline in VO2 and workload performance at peak and the ventilatory threshold on the second day, compared to all idiopathic chronic fatigue cases who were able to match or exceed their first day performance. The authors concluded that this decline in performance on the second day was disease-specific.<ref name=":6" /> A related comparison was performed for female patients with similar results.<ref>{{Cite journal|last=van Campen|first=C. (Linda) M. C.|last2=Visser|first2=Frans C.|date=Jun 2021|title=Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol|url=https://www.mdpi.com/2227-9032/9/6/682|journal=Healthcare|language=en|volume=9|issue=6|pages=682|doi=10.3390/healthcare9060682|pmc=|pmid=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=Linda van Campen|author-link2=Frans Visser|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> However there were several ICF patients that also had a reduction in peak workload and workload at the ventilatory threshold, despite the overall trend for an increase for ICF patients and a decrease for ME/CFS patients.

Unpublished studies have reported negative results for the repeated CPET procedure. In her thesis, Tessa-Maree Nielsen<ref>Nielsen TM. [https://mro.massey.ac.nz/bitstream/handle/10179/14653/02_whole.pdf?sequence=2&isAllowed=y The Timeline of Post Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. 2018.]</ref> at the Massey University, [[New Zealand]], performed the second exercise test 48 hours and 72 hours later, instead of the usual 24 hours. The study did not find significant reductions of workload at the ventilatory threshold in ME/CFS patients compared to controls. The eight ME/CFS patients in the 72 hours group had a workload at ventilatory threshold that was slightly higher instead of lower than during the first test. In a 2018 presentation,<ref>[https://www.youtube.com/watch?v=xpyz9K62Izg Presentation Ruud Vermeulen (03-06-2018). Minute 34.00.]</ref> Ruud Vermeulen reported to have data on approximately 500 ME/CFS patients who performed the repeated CPET procedure. He stated the test on the second day did not show any difference in VO2max compared to the first day, as shown in the graphs he presented.

Two-Day CPET studies have also considered other clinical groups, including [[Gulf War Illness|Gulf-War-Syndrome]]<ref>{{Cite journal|last=Lindheimer|first=Jacob B.|last2=Alexander|first2=Thomas|last3=Qian|first3=Wei|last4=Klein‐Adams|first4=Jacquelyn C.|last5=Lange|first5=Gudrun|last6=H. Natelson|first6=Benjamin|last7=Cook|first7=Dane B.|last8=Hill|first8=Helene Z.|last9=Falvo|first9=Michael J.|date=Sep 2020|title=An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue|url=https://onlinelibrary.wiley.com/doi/abs/10.14814/phy2.14564|journal=Physiological Reports|language=en|volume=8|issue=17|doi=10.14814/phy2.14564|pmid=32889791|pages=|quote=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=Gudrun Lange|author-link6=Benjamin Natelson|via=|pmc=|author-link7=Dane Cook}}</ref> and Sarcoidosis.<ref>{{Cite journal|last=Braam|first=A.W.E.|last2=de Haan|first2=S.N.|last3=Vorselaars|first3=A.D.M.|last4=Rijkers|first4=G.T.|last5=Grutters|first5=J.C.|last6=van den Elshout|first6=F.J.J.|last7=Korenromp|first7=I.H.E.|date=Oct 2013|title=Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis|url=https://linkinghub.elsevier.com/retrieve/pii/S0889159113001967|journal=Brain, Behavior, and Immunity|language=en|volume=33|pages=57–64|doi=10.1016/j.bbi.2013.05.006|issue=|pmc=|pmid=|quote=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> The study of Gulf-War-Syndrome patients did not reveal any significant group by time effects and in particular, no time effects at VT1. The study of Sarcoidosis patients did not find any group by time effects, however they focused on peak performance and ignored differences in performance at sub-maximal thresholds such as VT1. In addition, the study of Sarcoidosis patients did find an exercise effect on several biomarkers, however changes in these markers were not related to self-reported fatigue.

== Use as a Biomarker ==
[[Christopher Snell|Snell]] et al. suggested 2-day CPET could be used "diagnostically as an objective indicator of an abnormal postexertion response and possibly even a [[Diagnostic biomarker|biomarker]] for the condition."<ref name=":0" /> Using the data from the two exercise tests, their research team was able to correctly classify 95% of the total sample, as a patient or healthy control.

== Criticism ==
While a unique reduction in physiological capacity was observed in ME/CFS by several studies and different research groups, sample sizes were rather small and disagreement exists on which physiological measure accurately displayed ME/CFS patients’ [[Post-exertional malaise|abnormal exertional response]].<ref name=":1" />

Another objection to the 2-day CPET as a biomarker for ME/CFS was raised by Snell et al themselves. They suggested it might be unethical<ref name=":0" /> to use this method to detect ME/CFS patients since many of these patients might suffer relapse as a result of exercise testing. In their 2010 study, 60% of ME/CFS patients reported that it took them more than 5 days to recover from a single (maximal) CPET. It is therefore possible that in some ME/CFS patients a 2-day CPET might cause a long-lasting relapse. Science-reporter and ME/CFS patient [[Simon McGrath]] for example wrote: “You couldn’t pay me enough money to take even one max test. My last relapse, which took me nearly 2 years to get over, happened after way less than maximal [[exertion]] – a 2-day test is not for everyone."<ref>{{Cite news|url=https://www.healthrising.org/blog/2014/05/20/declining-production-exercise-study-reveal-broad-decline-energy-output-chronic-fatigue-syndrome/|title=Declining Production: Exercise Study Reveals Broad Declines in Energy Output in Chronic Fatigue Syndrome - Health Rising|date=2014-05-20|work=Health Rising|access-date=2018-08-17|language=en-US}}</ref>

Others have noted that the CPET-procedure is not very practical. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, it may not be available to most clinicians.<ref>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/03_Fatigue_Subgroup_CDE_Draft_Recommendations.pdf</ref> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref>{{Cite journal|last=Cotler|first=Joseph|last2=Holtzman|first2=Carly|last3=Dudun|first3=Catherine|last4=Jason|first4=Leonard A.|date=2018-09-11|title=A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref> For these reasons PEM is commonly assessed using self-reporting questionnaires.

[[Brian Vastag]] was able to prove his PEM was a severe symptom causing disability with CPET, winning his long term disability (LTD) claim.<ref name=":02">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/|title=Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability|last=Tillman|first=Adriane|authorlink=|last2=|first2=|authorlink2=|date=2018-06-04|website=#MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

==Cost and availability==
*[[Workwell Foundation]] (United States, CA)
*[[Betsy Keller]] at Ithaca College (United States, NY) Cost is $2200. Because they are based in a college setting (not healthcare setting), they cannot process insurance (including Medicare or Medicaid), so the patient would need to work directly with their insurer about reimbursement. (private email)
*[[Laura Black]] at Hunter-Hopkins Center, Charlotte, NC
*[[Open Medicine Institute]] Clinic
*[http://physiologic.com.au/ Physiologic 334 Scottsdale Drive, Robina, Gold Coast, Australia]
*[https://www.s4me.info/threads/uk-locations-that-offer-cpet-vo2max-testing.4999/ Many UK universities] offer standard CPETs which can be adapted for patients with ME.

==Talks and interviews==
*2013, [https://www.youtube.com/watch?v=fHulHdMPAd4 CPET Presentation by Dr. Christopher Snell, Part I][https://www.youtube.com/watch?v=piUDax7I-Ek CPET Presentation by Dr. Christopher Snell, Part II]
*2014, [https://www.youtube.com/watch?v=q_cnva7zyKM&feature=youtu.be Mark VanNess 'Exercise and ME/CFS' at Bristol Watershed. Part One]

==See also==

*[[Betsy Keller]]
*[[Christopher Snell]]
*[[Exercise]]
*[[Mark VanNess]]
*[[Post-exertional malaise]]
*[[Staci Stevens]]
==Learn more==

*[http://www.workwellfoundation.org/testing-for-disability/ The Workwell Foundation: Testing for Disability]
*2007, [http://www.name-us.org/MECFSExplainPages/2007CiccolellaLegalStressTest.pdf Legal and Scientific Considerations of the Exercise Stress Test]
*2013, [http://www.cortjohnson.org/blog/2013/07/30/busted-exercise-study-finds-energy-production-system-is-broken-in-chronic-fatigue-syndrome/ Busted! Exercise Study Finds Energy Production System is Broken in Chronic Fatigue Syndrome]
*2013, [http://phoenixrising.me/archives/17902/ Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity]
*2018, [https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ Victory For ME Disability Claim – U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability]<ref name=":02" />
*2019, [https://www.healthrising.org/blog/2019/01/17/decoding-2-day-cpet-chronic-fatigue-syndrome/ Decoding the 2-day Cardiopulmonary Exercise Test (CPET) in Chronic Fatigue Syndrome (ME/CFS)] by C. Christian

==References==
{{reflist}}
[[Category:Medical tests]]
[[Category:Cardiology]]

Exercise

2021-08-11T17:38:22Z

JenB:

'''Exercise''' is any movement or activity considered to contribute to general health and well-being. Exercise may be recommended as part of a wellness regimen in ''any'' chronic illness.<ref>{{Cite journal|last=Pederson|first=B.K.|last2=Saltin|first2=B.|date=2006|title=Evidence for prescribing exercise as therapy in chronic disease
|url=https://www.essa.org.au/wp-content/uploads/2015/06/Chronic-disease_Review-2006.pdf|journal=Scand J Med Sci Sports|volume=16|issue =Suppl 1|pages=3-63|via=}}</ref><ref>{{Cite journal|last=Hovanec|first=Nina|last2=Bellemore|first2=Derek|last3=Kuhnow|first3=Jason|last4=Miller|first4=Felicia|last5=van Vloten|first5=Alexi|last6=Vandervoort|first6=Anthony A.|date=3 March 2015|title=Exercise Prescription Considerations for Individuals with Multiple Chronic Diseases: Systematic Review|url=https://www.omicsonline.org/open-access/exercise-prescription-considerations-for-individuals-with-multiple-chronic-diseases-systematic-review-2167-7182-1000201.php?aid=41826|journal=J Gerontol Geriatr Resvolume = 4 | issue = 201 | pages =|via=}}</ref> However, [[Post-exertional malaise|exercise intolerance]] is a central feature of [[ME/CFS]], and patients show multiple documented abnormal responses to exercise, including significant worsening of all symptoms; this is the opposite response to how healthy people respond to exercise.<ref name="PEM2017" /> Rather than increase health and well-being, evidence from ME/CFS patients shows that exercise or even increased activity significantly reduces their physical ''and'' [[Cognitive dysfunction|mental capacity]] over time, sometimes permanently.<ref>{{Cite web|url=http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf|title=ME Association illness management report: no decisions about me without me|last=ME Association|first=|date=May 2015|website=ME Association|archive-url=|archive-date=|url-status=|access-date=25 April 2018}}</ref>

Worsening of symptoms in ME/CFS patients cannot be explained by [[deconditioning]] (lack of fitness), or by [[Cognitive behavioral model|psychological theories]] like "symptom focusing" or catastrophizing; the effects of exercise or over-exertion in patients include increased immune system symptoms, an increase in inflammatory markers in the blood, increased lactate in blood plasma, an increase in [[lactic acid]] in the muscles, and oxidative damage to DNA.<ref name="Fulle2000" />

==Physiological effects of exercise==

Exercise causes a variety of temporary physiological changes in healthy people. This includes an increase in respiratory rate, heart rate, and blood pressure in order to keep up with higher energy demands.<ref name=":0">{{Cite journal|last=Burton|first=Deborah Anne|last2=Stokes|first2=Keith|last3=Hall|first3=George M|date=December 1, 2004|title=Physiological effects of exercise|url=https://academic.oup.com/bjaed/article/4/6/185/314696|journal=Continuing Education in Anaesthesia Critical Care & Pain|publisher=|volume=4|issue=6|pages=185-8|via=BJA Education}}</ref> The chemical reactions that break down nutrients -- [[glycolysis]], the [[citric acid cycle]], and the [[electron transport chain]] -- move more rapidly to liberate energy, and blood flow to muscles should increase. In healthy individuals, the amount of [[oxygen]] and carbon dioxide present in the blood should not alter significantly.<ref name=":0" />

===Immune system===

In healthy people, exercise induces a variety of temporary changes to immune markers. Immediately after exercise, [[natural killer cell]] activity is decreased and [[Leukotriene]] B4 (LTB4) increase, along with the LTB4/PGE2 ratio. Exercise elevates levels of [[prostaglandin]] E2 (PGE2) for up to five days.<ref name="GrayJB1994" />

=== Infection ===
Several studies of a mouse model of [[Coxsackie B3]] [[myocarditis]] have found that exercise increases the virulence of the infection and results in poorer outcomes.<ref name=":4">Cabinian AE, Kiel RJ, Smith F, Ho KL, Khatib R, Reyes MR. Modification of exercise-aggravated coxsackie virus B3 murine myocarditis by T-lymphocyte suppression in an inbred model. J. Lab. Clin. Med. 1990; 115: 454– 62.</ref><ref name=":5">Kiel RJ, Smith FE, Chason J, Khatib R, Reyes MD. Coxsackie B3 myocarditis in C3H/HeJ mice: Description of an inbred model and the effect of exercise on the virulence. Eur. J. Epidemiol. 1989; 5: 248– 67.</ref><ref name=":6">{{Cite journal|last=Ilbäck|first=NG|date=June 1989|title=Exercise in coxsackie B3 myocarditis: Effects on heart lymphocyte subpopulations and the inflammatory reaction|url=https://www.ncbi.nlm.nih.gov/pubmed/2543197|journal=American Heart Journal|volume=117|pages=1298-302|via=}}</ref><ref name=":7">{{Cite journal|last=Gatmaitan|first=Bienvenido|date=June 1, 1970|title=Augmentation of the Virulence of Murine Coxsackie Virus B-3 Myocardiopathy by Exercise|url=http://jem.rupress.org/content/131/6/1121|journal=Journal of Experimental Medicine|volume=131|pages=1121|via=}}</ref><ref name=":8">{{Cite journal|last=Reyes|first=MP|date=February 1976|title=Interferon and neutralizing antibody in sera of exercised mice with coxsackievirus B-3 myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/1250870|journal=Proceedings of the Society for Experimental Biology and Medicine|volume=151|pages=333-8|via=}}</ref>

===Neurotransmitters===

[[Acetylcholine]], an important [[neurotransmitter]] that regulates immune response and muscle strength, decreases during exercise.

== Effects of exercise in Chronic Fatigue Syndrome ==

===Post Exertional Malaise===

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms, VanNess et al. (2010)|377x377px]]{{Main article|page_name=Post-exertional malaise}}[[File:2015 IOM report PEM chart.png|right|frame|PEM chart from the 2015 Institute of Medicine report|378x378px]]

[[ME]] patients who exercise are likely to experience [[Post-exertional malaise]], a worsening of symptoms following physical, cognitive, or sensory [[exertion]].

===Pain threshold===

Pain thresholds, or the point at which a stimulus becomes painful, drop in people with [[CFS]] (as per the [[Fukuda criteria]]) after graded exercise. In healthy controls, pain thresholds rise. This phenomenon has been attributed to a dysfunction of the central anti-[[nociceptive]] mechanism in [[CFS]] patients.<ref name="Whiteside, 2004" />

===Immune System===
[[Histamine]], a chemical that is released in response to cellular damage and inflammation, is released during exercise in healthy individuals. The histamine dilates blood vessels in order to deliver nutrients to working muscles.<ref>{{Cite journal|last=Romero|first=S.A.|last2=Hocker|first2=A.D.|last3=Magnum|first3=J.E.|last4=Luttrell|first4=M.J.|last5=Turnbull|first5=D.W. ...|last6=Halliwill|first6=J.R.|date=2016|title=Evidence of a broad histamine footprint on the human exercise transcriptome|url=http://doi.org/10.1113/JP272177|journal=The Journal of Physiology|volume=594|issue=17|pages=5009-5023|via=}}</ref> However, patients with ME may experience increased histamine release due to increased mast cell populations at baseline.<ref>{{Cite journal|last=Rönnberg|first=E|last2=Calounova|first2=G|last3=Pejler|first3=G|date=June 2017|title=Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients|url=https://www.ncbi.nlm.nih.gov/pubmed/27362406|journal=Asian Pac J Allergy Immunol|volume=35|issue=2|pages=75-81|via=}}</ref>

===Microbiome===

A small study of ten CFS patients found significant changes in the composition of the [[microbiome]] and increased bacterial translocation (movement from the [[intestine]] into the [[blood|bloodstream]]) following exercise. The study found increased ''[[Clostridium]]'' in the blood fifteen minutes after exercise and increased ''[[Bacilli]]'' 48 hours later.<ref name="ShuklaS2015" />

=== Musculature ===

Exercise has also been found to induce both early and excessive lactic acid formation in the [[muscle fatigability|muscles]]<ref name="Plioplys1995" /> with reduced intracellular concentrations of [[ATP]] and acceleration of [[glycolysis]].<ref name="McCully1996" /> Several studies have found abnormal increases in plasma lactate following short period of moderate exercise that cannot be explained by [[deconditioning]].<ref name="LaneRJ1998" /> There is evidence of abnormalities in pH handling by peripheral muscle, and possible evidence of an increased acidosis and lactate accumulation.<ref name="JonesDE2010" /><ref name="LengertN2015" />

There is also evidence of loss of capacity to recover from acidosis on repeat exercise.<ref name="JonesDE2012" />

Finally, there is evidence of abnormalities of [[AMPK]] activation and glucose uptake in cultured skeletal muscle cells in ME/CFS patients.<ref name="BrownAE2015" /><ref name="Wellness20150420" />
[[File:Light2011-geneexpression-figure3.jpg|right|frame|Gene expression changes following moderate exercise (Light et al, 2011)|516x516px]]
=== Gene expression ===

There is evidence of increased expression of certain genes following muscular exertion.<ref name="LightAR2009" /><ref name="LightAR2011" /><ref name="WhiteAT2012" /> A 2011 study found that moderate exercise in CFS increased the expression of 13 genes (sensory, adrenergic and 1 [[cytokine]]) for 48 hours, and the increases correlated with fatigue and pain levels (see graph at right).<ref name="LightAR2011" />

=== Second day exercise test ===
{{Main article|page_name =Two-day cardiopulmonary exercise testing}}

The seminal study on the response by CFS patients to a 2-day cardiopulmonary exercise test was published by [[Mark VanNess]], [[Christopher Snell]] and [[Staci Stevens]] in 2007: "Diminished Cardiopulmonary Capacity During Post-Exertional Malaise".<ref name="VanNess2007" /> While people with CFS responded similarly to healthy controls on a first test, on a follow-up 24 hours later, they were unable to replicate their original normal results. Instead, they had significantly lower values for VO2 peak and AT; these differences could be used to identify the CFS patient over 90% of the time. A repeat study in 2013 confirmed these results.<ref name="SnellCR2013" />

In a confirmation study, Doctor [[Betsy Keller]] also found that patients could not repeat their performance on a second cardiopulmonary exercise test performed a day after the first.<ref name="KellerBA2014" />

A review by [[Jo Nijs|Nijs]] et al. found that multiple studies showed reduced peak heart rate, reduced endurance, reduced peak work rate, reduced peak oxygen uptake, lower blood lactate values, and an increased respiratory exchange ratio in people with ME, ME/CFS, or CFS; see 'Oxidative impairment' below.<ref name="Nijs2014" />

It is important to note that CPET testing oxygen uptake (VO2), carbon dioxide output (VCO2), tidal volume (VT), blood pressure, and oxygen saturation are objective measures, and cannot be invalidated with inadequate effort.

===Oxidative impairment===

DeBecker et al (2000) and VanNess et al (2003) found low VO2 during exercise testing;<ref name="DeBecker2000" /><ref name="Vanness2003" /> Fulle et al. (2000) demonstrated oxidative damage to DNA<ref name="Fulle2000" />; and Wong et al. (1992) showed defects in oxidative metabolism and poor recovery of ATP after exercise.<ref name="Wong1992" />

== Graded exercise ==
{{main|page_name =Graded exercise therapy}}
Graded exercise therapy, or the incremental increase in physical activity over time, is a controversial treatment for ME/CFS, due to exercise intolerance being a central feature of the disease. See the main page for more.

== Excessive exercise ==
Excessive exercise in healthy people, particularly athletes, is known to cause [[overtraining syndrome]], which is often recognized by decreased exercise capacity. Overtraining syndrome has different signs and symptoms, effects of overtraining should not be confused with ME/CFS, which is a multi-systemic neurological illness with a different symptom profile and no known cure.{{Citation needed|reason=}}

==Talks and interviews==
*2009, [https://www.youtube.com/watch?v=vqy4gVNh0rI Staci Steven speaking to CFSAC meeting] ([[Staci Stevens]])
*2010, [http://www.hhs.gov/advcomcfs/meetings/presentations/presentation_10132010_snell-stevens.pdf Slide presentation to CFSAC] ([[Staci Stevens]], [[CFSAC]])
*2012, [https://www.youtube.com/watch?v=nL49DwGRs30 Clinical exercise testing in CFS/ME research and treatment] ([[Christopher Snell]])
*2012, [https://www.youtube.com/watch?v=kCO3pAbSq3I MECFS Alert Episode 32: Staci Stevens, Director of the Pacific Fatigue Lab] ([[Staci Stevens]], [[ME/CFS Alert]])
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be Top 10 Things You Should Know About Post-Exertional Relapse] ([[Staci Stevens]])
*2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)] ([[Lucinda Bateman]])
*2014, [https://www.youtube.com/watch?v=q_cnva7zyKM Mark VanNess 'Exercise and ME/CFS' at Bristol Watershed. Part One]<ref name="VanNess20140205video" /> ([[Mark VanNess]])
*2015, [https://www.youtube.com/watch?v=F1PP21TmUPs 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman]<ref name="Bateman20151103interview" /> ([[Lucinda Bateman]], [[Science for Patients]])
*2016, [https://www.youtube.com/watch?v=FXN6f53ba6k Dr. Mark Van Ness, "Expanding Physical Capability in ME/CFS" Part 1 (of 2)] ([[Mark VanNess]])
*2016, [https://www.youtube.com/watch?v=7BceGgEdMpA Dr. Mark Van Ness, "Expanding Physical Capability in ME/CFS" Part 2 (of 2)] ([[Mark VanNess]])

==Notable studies==
*2011, [[PACE trial]]
*2011, Tired of being inactive: a systematic literature review of physical activity, physiological exercise capacity and muscle strength in patients with chronic fatigue syndrome<ref>{{Cite journal|last=Nijs|first=Jo|author-link=Jo Nijs|last2=Aelbrecht|first2=Senne|author-link2=Senne Aelbrecht|last3=Meeus|first3=Mira|author-link3=Mira Meeus|last4=Van Oosterwijck|first4=Jessica|author-link4=Jessica Van Oosterwijck|last5=Zinzen|first5=Evert|author-link5=Evert Zinzen|last6=Clarys|first6=Peter|author-link6=Peter Clarys|date=2011|title=Tired of being inactive: a systematic literature review of physical activity, physiological exercise capacity and muscle strength in patients with chronic fatigue syndrome|url=http://emerge.org.au/wp-content/uploads/2014/11/Nijs-J.-et-al.-Tired-of-being-inactive.-Disabil-Rehabil-2011-3317-18.1493-1500.pdf|journal=Disability and Rehabilitation|volume=33|issue=17-18|pages=1493–1500|doi=10.3109/09638288.2010.541543|issn=1464-5165|pmid=21166613|quote=|via=}}</ref> [http://emerge.org.au/wp-content/uploads/2014/11/Nijs-J.-et-al.-Tired-of-being-inactive.-Disabil-Rehabil-2011-3317-18.1493-1500.pdf (Abstract)]
*2016, [https://www.ncbi.nlm.nih.gov/pubmed/27187093 Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis]
*2016, [[Cochrane|Cochrane meta-analysis]]
*2017, [https://www.sciencedirect.com/science/article/pii/S088915911730051X Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]<ref name="PEM2017">{{Cite journal|last=Cook|first=Dane B.|author-link=Dane Cook|last2=Light|first2=Alan R.|author-link2=Alan Light|last3=Light|first3=Kathleen C.|author-link3=Kathleen Broderick|last4=Broderick|first4=Gordon|author-link4=Gordon Broderick|last5=Shields|first5=Morgan R.|author-link5=Morgan Shields|last6=Dougherty|first6=Ryan J.|author-link6=Ryan Dougherty|last7=Meyer|first7=Jacob D.|author-link7=Jacob Meyer|last8=VanRiper|first8=Stephanie|author-link8=Stephanie Land|last9=Stegner|first9=Aaron J.|author-link9=Aaron Stegner|date=May 1, 2017|title=Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=http://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|volume=62|issue=|pages=87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591|quote=|via=}}</ref>
* 2020, Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patient<ref>{{Cite journal|last=Kujawski|first=Sławomir|author-link=|last2=Cossington|first2=Jo|author-link2=|last3=Słomko|first3=Joanna|author-link3=|last4=Dawes|first4=Helen|author-link4=|last5=Strong|first5=James W.L.|author-link5=|last6=Estevez-Lopez|first6=Fernando|author-link6=|last7=Murovska|first7=Modra|author-link7=Modra Murovska|last8=Newton|first8=Julia L.|author-link8=Julia Newton|last9=Hodges|first9=Lynette|date=2020-10-26|title=Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients|url=https://www.mdpi.com/2077-0383/9/11/3436|journal=Journal of Clinical Medicine|language=en|volume=9|issue=11|pages=3436|doi=10.3390/jcm9113436|issn=2077-0383|pmc = 7693605|pmid=33114704|access-date=|quote=|via=}}</ref> - [https://www.mdpi.com/2077-0383/9/11/3436/htm (Full text)]

==Learn more==
*2011 - [https://www.youtube.com/watch?v=Suq0dPMUbOk ME/CFS and Exercise: The VO2 Max Based Exercise Program, A Personal View] by [[Dan Moricoli]]
*Autumn 2011 - [http://www.meresearch.org.uk/our-research/completed-studies/acidosis/ Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case–control study], an essay for [[ME Research UK]]
*2014 - [https://www.youtube.com/watch?v=kbaW4JKkin4 ME/CFS and Exercise: VO2 Max Testing with Nancy Klimas M.D. - PREVIEW] (this is a preview of a pay-per-view video)
*May 16, 2014 - [http://www.deseretnews.com/article/865603384/Sufferers-of-chronic-fatigue-fibromyalgia-have-hope-in-new-diagnostic-tool.html Sufferers of chronic fatigue, fibromyalgia have hope in new diagnostic tool] by Wendy Leonard for ''Deseret News''<ref name="DeseretNews20140516" />
*Jan 17, 2015 - [http://sallyjustme.blogspot.co.uk/2015/01/dr-vanness-on-recent-press-reports.html Dr. VanNess on recent press reports] by Sally Burch in [[Just ME]] blog<ref name="BurchS20150117" />
*Nov 7, 2015 - [http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf Deviant Cellular and Physiological Responses to Exercise in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome] by [[Frank Twisk|Frank N.M. Twisk]], and [[Keith Geraghty|Keith J. Geraghty]]<ref name="TwiskF2015" />
*April 2015 - [https://www.omicsonline.org/open-access/objective-evidence-of-postexertional-malaise-in-myalgic-encephalomyelitis-and-chronic-fatigue-syndrome-2161-0673-1000159.pdf Objective Evidence of Post-exertional “Malaise” in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome] by Frank N.M. Twisk
*Dec 19, 2015 - [https://cfsremission.wordpress.com/2015/12/19/exercise-alteration-of-the-cfs-microbiome/ Exercise alteration of the CFS Microbiome] from [[CFS Remission]] blog
*Jan 2016 - [http://www.hindawi.com/journals/jar/2016/2497348/ Review Article: Understanding Muscle Dysfunction in Chronic Fatigue Syndrome] by Gina Rutherford, Philip Manning, and [[Julia Newton|Julia L. Newton]]<ref name="RutherfordG2016" />
*Feb 10, 2016 - [http://www.prohealth.com/library/showarticle.cfm?libid=25096 Lost in Translation - The ME-Polio Connection and the Dangers of Exercise] by [[Nancy Blake]] for ''[[ProHealth]]''<ref name="ProHealth20160210" />
*Jul 6, 2016 - [https://meaustralia.net/2016/07/06/australian-metabolomics-study-of-young-women/ Australian metabolomics study of young women with ME/CFS (CCC)] by Sasha Nimmo for ''ME Australia''
*Aug 12, 2016 - [http://solvecfs.org/neuromuscular-strain-in-mecfs-research-study-conclusion/ Neuromuscular Strain in ME/CFS – Research Study Conclusion] in [[Solve ME/CFS Initiative]] Newsletter
*Oct 2, 2017 - [https://www.npr.org/sections/health-shots/2017/10/02/554369327/for-people-with-chronic-fatigue-syndrome-more-exercise-isnt-better For People With Chronic Fatigue Syndrome, More Exercise Isn't Better - by Michaeleen Doucleff for ''Shots: Health News From NPR'']

== See also ==

*[[Two-day cardiopulmonary exercise testing]]
*[[Graded exercise therapy]]
*[[Muscle fatigability]]
*[[Mitochondrion]]
*[[Deconditioning]]
*[[Post-exertional malaise]]
*[[Body by Science]]

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| last1 = Wong | first1 = R | authorlink1 = Roger Wong
| last2 = Lopaschuk | first2 = G | authorlink2 = Gary Lopaschuk
| last3 = Zhu | first3 = G | authorlink3 = Gang Zhu
| last4 = Walker | first4 = D | authorlink4 = Dorothy Walker
| last5 = Catellier | first5 = D | authorlink5 = Dianne Catellier
| last6 = Burton | first6 = D | authorlink6 = David Burton
| last7 = Teo | first7 = K | authorlink7 = Koon Teo
| last8 = Collins-Nakai | first8 = R | authorlink8 = Ruth Collins-Nakai
| last9 = Montague | first9 = T | authorlink9 = Terrence Montague
| display-authors = 3
| title = Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy
| journal = Chest | issn = 0012-3692| volume = 102| issue = 6| pages = 1716–1722
| date = Dec 1992
| pmid = 1446478 | doi = 10.1378/chest.102.6.1716
| url = http://www.sciencedirect.com/science/article/pii/S0012369216408469
}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Psychological and behavioral therapies]]
[[Category:Energy system]]
[[Category:Depression alternative treatments]]
[[Category:Drug-free pain management]]

Epstein-Barr virus

2021-08-11T14:53:29Z

JenB:

{{Cleanup|reason=Add summary of the Notable studies from 2019 onwards|date=28 July 2020}}

[[The 3Ps model|The]] '''Epstein-Barr virus''' (EBV) or HHV4 is a [[herpesvirus]]. It is the most common cause of infectious [[mononucleosis]] or "glandular fever," and infects 90% of adults worldwide.<ref name="Saha2016" /> It has been implicated in numerous immune diseases and chronic illnesses, including [[chronic fatigue syndrome]], [[multiple sclerosis]], [[myasthenia gravis]], and [[systemic lupus erythematosus]]. It is known to turn on "risk genes" for autoimmune disease in the cells it infects.<ref name=":0">{{Cite journal|last=Harley|first=John|date= 16 April 2018|title=Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity|url=https://www.nature.com/articles/s41588-018-0102-3|journal=Nature genetics|volume=|pages=|via=|issue=|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=}}</ref><ref name=":1">{{Cite web|url=https://www.nih.gov/news-events/news-releases/epstein-barr-virus-protein-can-switch-risk-genes-autoimmune-diseases|title=Epstein-Barr virus protein can “switch on” risk genes for autoimmune diseases|last=|first=|date=16 April 2018|website=National Institutes of Health|archive-url=|archive-date=|url-status=|access-date=}}</ref>

== Initial infection ==
[[File:Epstein-barr virus (ebv).jpg|thumb|A stained sample of Epstein-Barr virus.]]
Symptoms of EBV infection include:
* [[fatigue]]

* [[fever]]
* [[rash]]
* inflamed [[sore throat|throat]]
* swollen [[lymph node]]s
* enlarged [[spleen]]
* swollen [[liver]]<ref name=":2">{{Cite web|url=http://www.cdc.gov/epstein-barr/about-ebv.html|title=Epstein-barr {{!}} Mononucleosis {{!}} About Virus {{!}} Mono {{!}} CDC|date=2018-05-10|website=[[Centers for Disease Control]]|language=en-us|access-date=2018-11-14}}</ref>

===Age of infection===

Most people acquire EBV in early childhood. Typically, young children who acquire EBV are either not symptomatic or have mild symptoms that are hard to distinguish from a cold or other other mild, childhood illnesses.

In adolescents and young adults, EBV can cause [[infectious mononucleosis]] (IM), also known as glandular fever.<ref name=":2" /> IM is characterized by [[fever]], [[sore throat]], swollen [[lymph node]]s, [[pain|body aches]], and [[fatigue]]. It generally resolves with rest and only rarely causes serious complications. It typically occurs in people who have not been exposed to EBV in early childhood, and in comparison, is more severe than infection in childhood (i.e., it can last for months).

Following initial infection, EBV can reactivate and has been shown to have many connections with various chronic illnesses. Relative to initial infections, reactivated EBV is much more severe.

==Transmission==

EBV is transmitted through [[bodily fluid]]s, most commonly through [[saliva]]. The first time a person is infected with EBV, the person is [[contagious]] for weeks (even when not displaying symptoms). The virus then transitions to the latent or inactive form, and stays in the body. If the virus reactivates, the person will be contagious again.<ref name=":2" />

== Diagnosis ==
EBV infection is confirmed with blood tests that detect presence of [[:Category:Antibodies|antibodies]]. Nine out of ten adults have these antibodies, indicating that they have a current or past EBV infection.<ref name=":2" />

Anti-VCA (Viral capsid antigen) IgG and EBV nuclear antigen (EBNA) IgG antibodies persist throughout a person's life. Thus, positive results merely indicate a current or past infection. A current EBV infection is diagnosed based on the presence of Anti-VCA IgM and Anti-EA (Early Antigen) IgG. VCA IgM appears early in EBV infection and usually disappears within four to six weeks. Positive VCA IgM suggests current active acute EBV infection. EA IgG appears in the acute phase of illness and generally falls to undetectable levels after three to six months. Positive EA IgG can suggest current active EBV infection or EBV re-activation. <ref>{{Cite web|url=https://www.cdc.gov/epstein-barr/laboratory-testing.html|title=Epstein-barr {{!}} Mononucleosis {{!}} Laboratory Testing {{!}} Mono {{!}} CDC|date=2019-01-28|website=[[Centers for Disease Control]]|language=en-us|access-date=2020-10-08}}</ref>

==Latency==

In healthy adults, the virus remains latent for life in memory [[B cell]]s. It is estimated that 1 in every one hundred thousand to one million circulating B cells carry EBV.<ref>{{Cite journal|last=Hsu|first=J. L.|last2=Glaser|first2=S. L.|date=Apr 2000|title=Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic implications|url=https://www.ncbi.nlm.nih.gov/pubmed/10781747/|journal=Critical Reviews in Oncology/Hematology|volume=34|issue=1|pages=27–53|issn=1040-8428|pmid=10781747}}</ref> In healthy hosts, EBV populations are kept in check by [[CD4]]+ and [[CD8]]+ [[T cell|T-cell]] responses.

The equilibrium can be disrupted in individuals with compromised [[immune system]]s such as patients with [[AIDS]] or transplant patients taking immune system suppressing drugs.<ref name=":3">{{Cite journal|last=Priatel|first=John J|last2=Chung|first2=Brian K|last3=Tsai|first3=Kevin|last4=Tan|first4=Rusung|date=2014-04-09|title=Natural killer T cell strategies to combat Epstein–Barr virus infection|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/|journal=Oncoimmunology|volume=3|doi=10.4161/onci.28329|issn=2162-4011|pmc=4063158|pmid=25050206|issue=|pages=|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|via=}}</ref> It has been observed that these patients are more susceptible to EBV-related cancers, such as certain [[lymphoma]]s and [[carcinoma]]s.<ref>{{Cite journal|last=Pattle|first=Samuel B.|last2=Farrell|first2=Paul J.|date=Nov 2006|title=The role of Epstein-Barr virus in cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/17049016|journal=Expert Opinion on Biological Therapy|volume=6|issue=11|pages=1193–1205|doi=10.1517/14712598.6.11.1193|issn=1744-7682|pmid=17049016|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|via=}}</ref> In immunocompromised patients, EBV can induce lymphoproliferation, [[lymphoma]], and [[hemophagocytic lymphohistiocytosis]] (HLH).<ref>{{Cite journal|last=Tangye|first=Stuart|date=January 20, 2017|title=Human immunity against EBV—lessons from the clinic|url=http://jem.rupress.org/content/214/2/269|journal=Journal of Experimental Medicine|volume=|pages=|via=|issue=|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=}}</ref>
===Natural killer T cells===

It is thought that [[natural killer T cell]]s (NKT) play a pivotal role in the control of EBV-infected B cells through their recognition of [[CD1d]] expressing cells.<ref name=":3" />

==Neuronal infection==
A 2015 study<ref name="JhaHC2015" /> demonstrated that human [[neuron]]al cells could be directly and actively infected with EBV and another [[herpesvirus]], Kaposi's sarcoma-associated herpesvirus (KSHV).

Neuronal cells were infected with EBV or KSHV viruses which had been combined with a fluorescent protein so that the infection could be observed. The infection was seen to produce new virus cells (productive) and spread efficiently. Significantly, it not only infected surrounding neuronal cells but also nearby [[Peripheral blood mononuclear cell|peripheral blood mononuclear cells]].

EBV is known to be linked to many neuronal diseases<ref name="Kleines2011" /> but this is the first evidence of how this may occur. The researchers note that this research supports the presence of EBV in neuronal diseases, but does not indicate why this is so.

==In human disease==

Epstein-Barr virus has been associated with a wide number of immune diseases including [[multiple sclerosis]], [[rheumatoid arthritis]], [[systemic lupus erythematosus]],<ref>{{Cite journal|last=Lossius|first=Andreas|date=December 2012|title=Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528287/|journal=Virus|volume=|pages=|via=|issue=|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=}}</ref> [[Chronic fatigue syndrome]], and [[myasthenia gravis]]. EBV was recently discovered to turn on "risk genes" for autoimmune disease in the cells it infects. [[EBNA]]2, a protein produced by EBV-infected cells, and its related transcription factors activate half the human genes known to be associated with the risk for lupus as well as genes associated with several other autoimmune diseases including [[multiple sclerosis]], [[rheumatoid arthritis]], [[inflammatory bowel disease]], [[Diabetes#Types|type 1 diabetes]], [[juvenile idiopathic arthritis]] and [[celiac disease]]. EBV activation can thus increase the risk of developing these diseases.<ref name=":0" /><ref name=":1" />

===Chronic fatigue syndrome===

A prospective study of 250 primary care patients revealed a higher prevalence of [[chronic fatigue syndrome]] after infectious [[mononucleosis]] (glandular fever) when compared to an ordinary upper respiratory tract infection.<ref name=":4">{{Cite journal|last=White|first=P. D.|last2=Thomas|first2=J. M.|last3=Amess|first3=J.|last4=Crawford|first4=D. H.|last5=Grover|first5=S. A.|last6=Kangro|first6=H. O.|last7=Clare|first7=A. W.|date=Dec 1998|title=Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever|url=https://www.ncbi.nlm.nih.gov/pubmed/9926075|journal=The British Journal of Psychiatry: The Journal of Mental Science|volume=173|pages=475–481|issn=0007-1250|pmid=9926075}}</ref> Anti-early antigen titers to EBV were elevated in CFS patients and associated with worse symptoms.<ref name=":5">{{Cite journal|last=Schmaling|first=K. B.|last2=Jones|first2=J. F.|date=Jan 1996|title=MMPI profiles of patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8730646|journal=Journal of Psychosomatic Research|volume=40|issue=1|pages=67–74|issn=0022-3999|pmid=8730646}}</ref> A 2006 Australian prospective study found that 12% of subjects infected by EBV met the criteria for [[Chronic fatigue syndrome]] six months after their infection, and 9% still had CFS 12 months after infection.<ref name=":6">{{Cite journal|last=Hickie|first=Ian|author-link=Ian Hickie|last2=Davenport|first2=Tracey|author-link2=Tracey Davenport|last3=Wakefield|first3=Denis|author-link3=Denis Wakefield|last4=Vollmer-Conna|first4=Ute|author-link4=Uté Vollmer-Conna|last5=Cameron|first5=Barbara|author-link5=Barbara Cameron|last6=Vernon|first6=Suzanne D|author-link6=Suzanne Vernon|last7=Reeves|first7=William C|author-link7=William Reeves|last8=Lloyd|first8=Andrew|author-link8=Andrew Lloyd|date=2006-09-16|title=Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569956/|journal=BMJ : British Medical Journal|volume=333|issue=7568|pages=575|doi=10.1136/bmj.38933.585764.AE|issn=0959-8138|pmc=1569956|pmid=16950834|access-date=|quote=|via=}}</ref> (The same rate held true for [[Ross River virus]] and [[Q fever]]).

=== Long COVID ===
Long COVID may be associated [[herpesvirus]] reactivation such as Epstein-Barr Virus.<ref>{{Cite journal|last=Proal|first=Amy D.|last2=VanElzakker|first2=Michael B.|date=2021|title=Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms|url=https://www.frontiersin.org/articles/10.3389/fmicb.2021.698169/full|journal=Frontiers in Microbiology|language=English|volume=0|doi=10.3389/fmicb.2021.698169|issn=1664-302X}}</ref>

===Multiple sclerosis===

Infection later in life, high serum titers against EBV, and [[mononucleosis]] have all been associated with an increased risk of multiple sclerosis. MS relapses are correlated with EBV reactivation.<ref>{{Cite journal|last=Holmøy|first=Trygve|date=2008|title=Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis|url=http://www.sciencedirect.com/science/article/pii/S0306987707003167|journal=Medical Hypotheses|volume=70|pages=|via=}}</ref>

Several studies by Alberto Ascherio, MD, DrPH, and his team at the Harvard School of Public Health have suggested that Epstein-Barr virus is involved in [[multiple sclerosis]], specifically in people with a certain immune-related gene and high levels of antibodies to EBV in their blood.<ref>{{Cite web|url=https://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses|title=Viruses|last=|first=|date=|website=National Multiple Sclerosis Society|archive-url=|archive-date=|url-status=|access-date=2018-11-14}}</ref>

=== Systemic lupus erythematosus ===
In a study of young patients with lupus, 99% had EBV as compared to 70% of healthy controls.<ref>{{Cite journal|last=James|first=JA|date=1997-12-15|title=An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus|url=https://www.jci.org/articles/view/119856|journal=The Journal of Clinical Investigation|volume=|pages=|via=}}</ref> Another study found that patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, likely stemming from altered [[t cell]] responses against EBV.<ref>{{Cite journal|last=Kang|first=Insoo|date=15 January 2004|title=Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus|url=http://www.jimmunol.org/content/172/2/1287.short|journal=The Journal of Immunology|volume=|pages=|via=}}</ref>

===Myasthenia gravis===

[[B cell]]s from [[myasthenia gravis]] patient stimulated ''in vitro'' by Epstein-Barr virus produced [[acetylcholine]] autoantibodies.<ref>{{Cite journal|last=Brenner|first=T.|last2=Timore|first2=Y.|last3=Wirguin|first3=I.|last4=Abramsky|first4=O.|last5=Steinitz|first5=M.|date=Oct 1989|title=In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis|url=https://www.ncbi.nlm.nih.gov/pubmed/2553772|journal=Journal of Neuroimmunology|volume=24|issue=3|pages=217–222|issn=0165-5728|pmid=2553772}}</ref> Ongoing EBV infection of the [[thymus]] has been posited as a causative agent for the production of [[acetylcholine]] receptor autoantibodies in [[myasthenia gravis]].<ref>{{Cite journal|last=Kaminski|first=Henry J|last2=Minarovits|first2=Janos|title=Epstein-barr virus: Trigger for autoimmunity?|url=http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/|journal=Annals of Neurology|language=en|issn=0364-5134|date=2010|issue=6|doi=|pages=697-698|pmc=|pmid=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=|volume=67}}</ref><ref>{{Cite web|url=http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10|title=Official Brain & Life Home Page|website=journals.lww.com|language=en|access-date=2018-11-15}}</ref>

=== Gastrointestinal disease ===
One study of EBV in patients with [[gastritis]], [[Crohn's disease]], and [[ulcerative colitis]] and normal controls found essentially undetectable levels of EBV in normal gastric mucosa. However, EBV was detected in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn’s disease, and 64% of ulcerative colitis samples.<ref>{{Cite journal|last=Ryan|first=Julie|date=2013|title=Epstein-Barr Virus Infection is Common in Inflamed Gastrointestinal Mucosa|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535492/|journal=Dig Dis Sci.|volume=|pages=|via=}}</ref>

===Lyme disease===

Several herpesviruses including Epstein-Barr virus<ref name="Goossens1999" /> may cause false positives on [[Lyme disease]] tests.

===X-MEN Disease===

A 2014 study found chronic Epstein-Barr infection was linked to a magnesium transporter ([https://www.ncbi.nlm.nih.gov/gene/84061 MAGT-1]) mutation. Dysfunction in this transporter also resulted in decreased NK cell function, and neoplasia (sometimes-cancerous growths).<ref name="X-men_disease_1" /> This disorder, termed 'X-MEN' (for X-linked, EBV, and neoplasia) was identified as a [https://en.wikipedia.org/wiki/X-linked_recessive_inheritance recessive, X-linked disorder] that would therefore be many times more common in men.

Since chronic Epstein-Barr virus infection has been associated with chronic fatigue syndrome, this error in [[magnesium]] transport may be worth considering in male patients, especially with slow onset and history of childhood infection.<ref name="X-men_disease_1" /><ref name="X-men_disease_2" /> However, in this disorder, EBV would be seen as an indicator of the illness rather than the cause.

==Vitamin D==

Some recent research is finding links between EBV and [[Vitamin D]]

An Epstein-Barr virus protein EBNA-3 has an affinity for [[VDR]] and may actually block the activation of VDR-dependent genes by [[Vitamin D]].<ref>{{Cite journal|last=Yenamandra|first=Surya Pavan|last2=Hellman|first2=Ulf|last3=Kempkes|first3=Bettina|last4=Darekar|first4=Suhas Deoram|last5=Petermann|first5=Sabine|last6=Sculley|first6=Tom|last7=Klein|first7=George|last8=Kashuba|first8=Elena|date=Dec 2010|title=Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes|url=https://www.ncbi.nlm.nih.gov/pubmed/20593215|journal=Cellular and molecular life sciences: CMLS|volume=67|issue=24|pages=4249–4256|doi=10.1007/s00018-010-0441-4|issn=1420-9071|pmid=20593215}}</ref>

[[Vitamin D receptor]] may be required for the normal development of [[natural killer T cell]]s that react to cells expressing [[CD1d]], as in cells infected by EBV.<ref>{{Cite journal|last=Yu|first=Sanhong|last2=Cantorna|first2=Margherita T.|date=2008-04-01|title=The vitamin D receptor is required for iNKT cell development|url=http://www.pnas.org/content/105/13/5207|journal=Proceedings of the National Academy of Sciences|language=en|volume=105|issue=13|pages=5207–5212|doi=10.1073/pnas.0711558105|issn=0027-8424|pmid=18364394}}</ref>

As low Vitamin D is also a risk factor for MS, some studies have attempt to find a link between low Vitamin D status, EBV and MS. One study of healthy individuals found no link between EBV load and Vitamin D status. However, over half the subjects were Vitamin D deficient and none had optimal levels<ref>{{Cite journal|last=Ramien|first=Caren|last2=Pachnio|first2=Annette|last3=Sisay|first3=Sofia|last4=Begum|first4=Jusnara|last5=Leese|first5=Alison|last6=Disanto|first6=Giulio|last7=Kuhle|first7=Jens|last8=Giovannoni|first8=Gavin|last9=Rickinson|first9=Alan|date=May 2014|title=Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort|url=https://www.ncbi.nlm.nih.gov/pubmed/24192216?dopt=Abstract|journal=Multiple Sclerosis (Houndmills, Basingstoke, England)|volume=20|issue=6|pages=751–753|doi=10.1177/1352458513509507|issn=1477-0970|pmid=24192216}}</ref> (i.e., above 100 nmol/l).

==Treatment==

There is no specific treatment for EBV, only treatment of symptoms, such as taking over-the-counter medications for pain and fever.<ref name=":2" /> EBV is thought to persistent harmlessly in immunocompetent individuals, but in those with compromised immune systems it has been associated with certain cancers and possibly autoimmune disease.

===Antivirals===

Several [[antiviral]]s are active against EBV including [[valganciclovir|valganciclovir,]] [[valacyclovir]]<ref>{{Cite journal|last=Hoshino|first=Yo|date=|title=Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers|url=http://jvi.asm.org/content/83/22/11857.full|journal=Journal of Virology|volume=|pages=|via=}}</ref>, [[acyclovir]]<ref>{{Cite journal|last=Rafaillidis|first=Pl|date=Nov 2013|title=Antiviral treatment for severe EBV infections in apparently immunocompetent patients|url=https://www.ncbi.nlm.nih.gov/pubmed/20739216|journal=Journal of Clinical Virology|volume=|pages=|via=}}</ref> and [[spironolactone]].<ref name="Verma2016" />

[[Acyclovir]], an [[antiviral]] drug which inhibits (but does not destroy) herpesviruses, was shown to also inhibit the virus production. This suggests that EBV replicates via lytic replication.

A theoretical [[immunotherapy]] treatment proposes that inducing [[CD1d]] expression on EBV-infected B cells could prompt effective immune suppression of EBV by NKT cells.<ref>{{Cite journal|last=Priatel|first=John J|last2=Chung|first2=Brian K|last3=Tsai|first3=Kevin|last4=Tan|first4=Rusung|date=2014-04-09|title=Natural killer T cell strategies to combat Epstein–Barr virus infection|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/|journal=Oncoimmunology|volume=3|doi=10.4161/onci.28329|issn=2162-4011|pmc=4063158|pmid=25050206}}</ref>

===Rituximab===

[[Rituximab]] may be effective in completely eliminating Epstein-Barr virus infection from the peripheral blood.<ref>{{Cite journal|last=Diamantopoulos|first=Panagiotis T.|last2=Polonyfi|first2=Katerina|last3=Sofotasiou|first3=Maria|last4=Papadopoulou|first4=Vasiliki|last5=Kalala|first5=Fani|last6=Iliakis|first6=Theodoros|last7=Zervakis|first7=Kostantinos|last8=Tsilimidos|first8=Gerassimos|last9=Kouzis|first9=Panagiotis|date=Dec 2013|title=Rituximab in the treatment of EBV-positive low grade B-cell lymphoma|url=https://www.ncbi.nlm.nih.gov/pubmed/24324119|journal=Anticancer Research|volume=33|issue=12|pages=5693–5698|issn=1791-7530|pmid=24324119}}</ref> A study of seventeen patients with low-grade [[B cell]] lymphoma found that after three cycles of Rituximab, the virus had been completely eliminated from the peripheral blood in all but one patient.

===Herbs and nutraceuticals===

Herbs shown to have antiviral properties against EBV including [[licorice|licorice.]]<ref>{{Cite journal|last=Lin|first=Jung-Chung|last2=Cherng|first2=Jaw-Ming|last3=Hung|first3=Man-Shan|last4=Baltina|first4=Lidia A.|last5=Baltina|first5=Lia|last6=Kondratenko|first6=Rimma|date=Jul 2008|title=Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure-activity relationships|url=https://www.ncbi.nlm.nih.gov/pubmed/18423902|journal=Antiviral Research|volume=79|issue=1|pages=6–11|doi=10.1016/j.antiviral.2008.01.160|issn=0166-3542|pmid=18423902}}</ref> [[Vitamin C]] and Vitamin D<ref>{{Cite journal|last=Rolf|first=L|date=July 2017|title=Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/28731372|journal=Multiple Sclerosis|volume=|pages=|via=}}</ref> might also decrease duration and severity of the symptoms of EBV infection.<ref>{{Cite journal|last=Mikirova|first=N|date=May 2014|title=Effect of high dose vitamin C on Epstein-Barr viral infection|url=https://www.ncbi.nlm.nih.gov/pubmed/24793092|journal=Med Sci Monit|volume=|pages=|via=}}</ref>

===Vaccine===
A [[vaccine]] for the prevention of Epstein-Barr virus is being explored.<ref>{{Cite web|url=https://www.nih.gov/news-events/news-releases/nih-researchers-make-progress-toward-epstein-barr-virus-vaccine|title=NIH researchers make progress toward Epstein-Barr virus vaccine|date=2019-04-09|website=National Institutes of Health (NIH)|language=EN|access-date=2019-04-10}}</ref>

==Notable studies==
*1996, MMPI profiles of patients with chronic fatigue syndrome<ref name=":5" /> - ([[pubmed:8730646|Abstract]])
*1998, Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever<ref name=":4" /> - ([[pubmed:9926075|Abstract]])
*2006, Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study<ref name=":6" /> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569956/ (Full text)]
*2019, EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection<ref>{{Cite journal|last=Asprusten|first=Tarjei Tørre|last2=Pedersen|first2=Maria|last3=Skovlund|first3=Eva|last4=Wyller|first4=Vegard Bruun|date=2019|title=EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection|url=https://www.ncbi.nlm.nih.gov/pubmed/30957026|journal=BMJ paediatrics open|volume=3|issue=1|pages=e000390|doi=10.1136/bmjpo-2018-000390|issn=2399-9772|pmc=|pmid=30957026|quote=|author-link=Tarjei Tørre Asprusten|author-link2=Maria Pedersen|author-link3=Eva Skovlund|author-link4=Vegard Bruun Wyller|author-link5=|via=}}</ref> - ([[pubmed:30957026|Abstract]])
*2019, Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study<ref>{{Cite journal|last=Pedersen|first=Maria|last2=Asprusten|first2=Tarjei Tørre|last3=Godang|first3=Kristin|last4=Leegaard|first4=Truls Michael|last5=Osnes|first5=Liv Toril|last6=Skovlund|first6=Eva|last7=Tjade|first7=Trygve|last8=Øie|first8=Merete Glenne|last9=Wyller|first9=Vegard Bruun Bratholm|date=Jan 2019|title=Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study|url=https://www.ncbi.nlm.nih.gov/pubmed/30261303|journal=Brain, Behavior, and Immunity|volume=75|pages=94–100|doi=10.1016/j.bbi.2018.09.023|issn=1090-2139|pmid=30261303|issue=|quote=|author-link=Maria Pedersen|author-link2=Tarjei Tørre Asprusten|author-link3=Kristin Godang|author-link4=Truls Michael Leegaard|author-link5=Liv Toril Osnes|via=|author-link7=Trygve Tjade|author-link6=Eva Skovlund|author-link8=Merete Glenne Øie|author-link9=Vegard Bruun Wyller}}</ref> - ([[pubmed:30261303|Abstract]])
*2019, Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later<ref>{{Cite journal|last=Pedersen|first=Maria|last2=Asprusten|first2=Tarjei Tørre|last3=Godang|first3=Kristin|last4=Leegaard|first4=Truls Michael|last5=Osnes|first5=Liv Toril|last6=Skovlund|first6=Eva|last7=Tjade|first7=Trygve|last8=Øie|first8=Merete Glenne|last9=Wyller|first9=Vegard Bruun Bratholm|date=2019-01-27|title=Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later|url=https://www.ncbi.nlm.nih.gov/pubmed/30685875|journal=Acta Paediatrica (Oslo, Norway: 1992)|doi=10.1111/apa.14728|issn=1651-2227|pmid=30685875|issue=|pages=|quote=|author-link=Maria Pedersen|author-link2=Tarjei Tørre Asprusten|author-link3=Kristin Godang|author-link4=Truls Michael Leegaard|author-link5=Liv Toril Osnes|via=|volume=|author-link6=Eva Skovlund|author-link7=Trygve Tjade|author-link8=Merete Glenne Øie|author-link9=Vegard Bruun Wyller}}</ref> - ([[pubmed:30685875|Abstract]])
*2019, Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref>{{Cite journal|last=Williams|first=Marshall V.|author-link=|last2=Cox|first2=Brandon|author-link2=|last3=Lafuse|first3=William P.|author-link3=|last4=Ariza|first4=Maria Eugenia|author-link4=|author-link5=|date=May 2019|title=Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://linkinghub.elsevier.com/retrieve/pii/S0149291819301730|journal=Clinical Therapeutics|language=en|volume=41|issue=5|pages=848–863|doi=10.1016/j.clinthera.2019.04.009|pmc=6525645|pmid=31040055|quote=|via=}}</ref> - ([https://www.clinicaltherapeutics.com/article/S0149-2918(19)30173-0/fulltext Full text)]
*2019, Review article - [[Epstein-Barr virus]] induced gene-2 upregulation identifies a particular subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis<ref name="Kerr2019EBV">{{Cite journal|last=Kerr|first=Jonathan R.|author-link=Jonathan Kerr|author-link2=|author-link3=|author-link4=|author-link5=|date=Feb 2019|title=Epstein-Barr virus induced gene-2 upregulation identifies a particular subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis|url=https://www.frontiersin.org/articles/10.3389/fped.2019.00059/abstract|journal=Frontiers in Pediatrics|volume=|issue=|pages=|doi=10.3389/fped.2019.00059|quote=|via=}}</ref> - [https://www.frontiersin.org/articles/10.3389/fped.2019.00059/full (Full text)]
*2019, Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors<ref name="Kerr2019a">{{Cite journal|last=Kerr|first=Jonathan R|author-link=Jonathan Kerr|author-link2=|author-link3=|author-link4=|author-link5=|author-link6=|date=2019-07-17|title=Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors|url=http://jcp.bmj.com/lookup/doi/10.1136/jclinpath-2019-205822|journal=Journal of Clinical Pathology|language=en|volume=|issue=|pages=jclinpath–2019–205822|doi=10.1136/jclinpath-2019-205822|issn=0021-9746|quote=|via=}}</ref> - [[pubmed:31315893|(Abstract)]]
*2020, Cytomegalovirus, Epstein-Barr Virus, and Human herpesvirus-6 Infections in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Shikova2020">{{Cite journal|last=Shikova|first=Evelina|author-link=|last2=Reshkova|first2=Valentina|author-link2=|last3=Kumanova|first3=Аntoniya|author-link3=|last4=Raleva|first4=Sevdalina|author-link4=|last5=Alexandrova|first5=Dora|author-link5=|last6=Capo|first6=Natasa|author-link6=|last7=Murovska|first7=Modra|last8=|first8=|date=2020|title=Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25744|journal=Journal of Medical Virology|language=en|volume=|issue=|pages=|doi=10.1002/jmv.25744|issn=1096-9071|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.1002/jmv.25744 (Abstract)]

== See also ==
* [[List of herpesvirus infection studies]]

==References==

<references>
<ref name="Goossens1999">{{citation
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| last2 = Nohlmans | first2 = MK
| last3 = van den Bogaard | first3 = AE
| title = Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis
| journal = Infection | issue = 1999 | volume = 27 | pages =231
| pmid = 10378140
| url = https://www.ncbi.nlm.nih.gov/pubmed/10378140
}}</ref>
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| last2 = Mehta | first2 = D | authorlink2 =
| last3 = Lu | first3 = J | authorlink3 =
| last4 = El-Naccache | first4 = D | authorlink4 =
| last5 = Shukla | first5 = SK | authorlink5 =
| last6 = Kovacsics | first6 = C | authorlink6 =
| last7 = Kolson | first7 = D | authorlink7 =
| last8 = Robertson | first8 = ES | authorlink8 =
| display-authors = 2
| title = Gammaherpesvirus Infection of Human Neuronal Cells
| journal = mBio | volume = 6 | issue =6 | page =
| date = 2016-12-01
| doi = 10.1128/mBio.01844-15 | pmid = 26628726
| url = http://mbio.asm.org/content/6/6/e01844-15
}}</ref>
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| last2 = Schiefer | first2 = J
| last3 = Stienen | first3 = A
| last4 = Blaum | first4 = M
| last5 = Ritter | first5 = K
| last6 = Häusler | first6 = M
| title = Expanding the spectrum of neurological disease associated with Epstein-Barr virus activity
| journal = European Journal of Clinical Microbiology & Infectious Diseases
| issn = 1435-4373| volume = 30| issue = 12| pages = 1561–1569
| date = 2011-05-15
| doi = 10.1007/s10096-011-1261-7
| url = http://link.springer.com/article/10.1007/s10096-011-1261-7
}}</ref>
<ref name="Saha2016">{{citation
| last1 = Saha | first1 = Abhik
| last2 = Robertson | first2 = Erle S
| title = Epstein-Barr Virus–Associated B-cell Lymphomas: Pathogenesis and Clinical Outcomes
| journal = Clinical Cancer Research
| issn = 1557-3265| volume = 17| issue = 10| pages = 3056–3063
| date = 2011-05-15
| pmid = 21372216 | doi = 10.1158/1078-0432.CCR-10-2578
| url = http://clincancerres.aacrjournals.org/content/17/10/3056
}}</ref>
<ref name="Verma2016">{{citation
| last1 = Verma | first1 = Dinesh
| last2 = Thompson | first2 = Jacob
| last3 = Swaminathan | first3 = Sankar
| title = Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function
| journal = Proceedings of the National Academy of Sciences
| issn = 1091-6490 | volume = 113| issue = 13| pages = 3609–3614
| date = 2016-03-29
| doi = 10.1073/pnas.1523686113 | pmid = 26976570
| url = http://www.pnas.org/content/113/13/3609
}}</ref>
<ref name="X-men_disease_1">{{Citation
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| first1 = F.-Y.
| authorlink1 =
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| last4 = Matthews
| first4 = H
| last5 = Lenardo
| first5 = M.J.
| authorlink3 =
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| title = XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.
| journal = Blood
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</ref>
</references>

[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]

Long COVID pathophysiology

2021-08-11T14:46:46Z

JenB:

'''[[Long COVID]]''', '''long tail covid''', '''Post-Acute Sequelae of COVID-19''' '''(PASC)''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.

== Overview ==
{{Main article|page_name=Long COVID}}

== Pathophysiology ==

=== Infection and immunity ===
A range of [[Antibody|antibodies]] have been found in patients with persistent post-acute COVID symptoms. Elevated [[G-protein coupled receptor]] autoantibodies have been found.<ref>{{Cite journal|date=2021-01-01|title=Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms|url=https://www.sciencedirect.com/science/article/pii/S2589909021000204|journal=Journal of Translational Autoimmunity|language=en|volume=4|pages=100100|doi=10.1016/j.jtauto.2021.100100|issn=2589-9090}}</ref> One study founded elevated [[antinuclear antibody]] (ANA) titles in 43.6% of long COVID patients twelve months after symptom onset.<ref>{{Cite journal|last=Seeßle|first=Jessica|last2=Waterboer|first2=Tim|last3=Hippchen|first3=Theresa|last4=Simon|first4=Julia|last5=Kirchner|first5=Marietta|last6=Lim|first6=Adeline|last7=Müller|first7=Barbara|last8=Merle|first8=Uta|date=2021-07-05|title=Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study|url=https://doi.org/10.1093/cid/ciab611|journal=Clinical Infectious Diseases|issue=ciab611|doi=10.1093/cid/ciab611|issn=1058-4838}}</ref>

Long COVID may be associated [[herpesvirus]] reactivation such as [[Epstein-Barr virus|Epstein-Barr Virus]],<ref>{{Cite journal|last=Gold|first=Jeffrey E.|last2=Okyay|first2=Ramazan A.|last3=Licht|first3=Warren E.|last4=Hurley|first4=David J.|date=2021/6|title=Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation|url=https://www.mdpi.com/2076-0817/10/6/763|journal=Pathogens|language=en|volume=10|issue=6|pages=763|doi=10.3390/pathogens10060763}}</ref> which has been shown to cause elevations of certain G-protein coupled receptor autoantibody types.<ref>{{cite book|last1=Angelini|first1=Lucia|last2=Bardare|first2=Maria|last3=Martini|first3=Alberto|year=2002|title=Immune-mediated Disorders of the Central Nervous System in Children|url=https://books.google.com/books?id=5trQOK8hcZUC&pg=PA7&lpg=PA7&dq=coxsackie+b+acetylcholine&source=bl&ots=zhup8ZXq68&sig=CxDwQCHO8-OMBYkcp4EayjnDKnw&hl=en&sa=X&ved=0ahUKEwjflpmqg9fOAhWBeSYKHSR4Dh0Q6AEIMTAD#v=onepage&q=coxsackie%20b%20acetylcholine&f=false}}</ref><ref>{{Cite journal|last=Gebhardt|first=B. M.|date=2000-06-26|title=Evidence for antigenic cross-reactivity between herpesvirus and the acetylcholine receptor|url=http://www.ncbi.nlm.nih.gov/pubmed/10742556|journal=Journal of Neuroimmunology|volume=105|issue=2|pages=145–153|issn=0165-5728|pmid=10742556}}</ref><ref>{{Cite journal|last=Brenner|first=T.|last2=Timore|first2=Y.|last3=Wirguin|first3=I.|last4=Abramsky|first4=O.|last5=Steinitz|first5=M.|date=Oct 1989|title=In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis|url=http://www.ncbi.nlm.nih.gov/pubmed/2553772|journal=Journal of Neuroimmunology|volume=24|issue=3|pages=217–222|issn=0165-5728|pmid=2553772}}</ref><ref>{{Cite journal|last=Kaminski|first=Henry J.|last2=Janos|first2=Minarovits|title=Epstein-barr virus: Trigger for autoimmunity?|url=http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/|journal=Annals of Neurology|language=en|issn=0364-5134}}</ref><ref>{{Cite web|url=http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10|title=Official Brain & Life Home Page|website=journals.lww.com|language=en|access-date=2018-08-10}}</ref>

=== Neurological and neuropsychiatric ===

=== Cardiovascular ===

=== Pulmonary ===

== Comparison to other conditions ==

=== Post-acute SARS ===

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

=== POTS ===
{{Main|page_name=Postural orthostatic tachycardia syndrome}}

=== MCAS ===
{{Main|page_name=Mast cell activation syndrome}}

=== Alzheimer’s ===

=== Traumatic Brain Injury ===
{| class="wikitable"
!Findings
!Long COVID
!Post-acute SARS
!ME/CFS
!POTS
!MCAS
|-
|G-protein coupled receptor autoantibodies
|β2- and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, nociceptin- and ETA-receptors
|
|M3 and M4 [[Muscarinic acetylcholine receptor|muscarinic acetylcholine receptors]], as well as ß2 [[Adrenergic receptor|adrenergic receptors]]
|α1, β1 and β2 adrenergic receptor autoantibodies
|
|-
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|}

== See also ==
* [[Long COVID]]

== Learn more ==
* [https://docs.google.com/spreadsheets/d/1gF-kMUxJWNrwxbmoMW2wGKTMlksRUAROjh7b97G9IE8/edit Long COVID Resource Hub] (database of Long COVID research)

== References ==
<references />

Long COVID pathophysiology

2021-08-11T14:41:28Z

JenB:

Long COVID pathophysiology

2021-08-11T14:29:09Z

JenB:

Long COVID pathophysiology

2021-08-11T14:18:37Z

JenB:

Long COVID pathophysiology

2021-08-11T14:13:03Z

JenB:

=== Infection and immunity ===

=== Neurological and neuropsychiatric ===

=== Cardiovascular ===

== Comparison to other conditions ==

=== Post-acute SARS ===

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

=== POTS ===
{{Main|page_name=Postural orthostatic tachycardia syndrome}}

=== MCAS ===
{{Main|page_name=Mast cell activation syndrome}}

=== Alzheimer’s ===

=== Traumatic Brain Injury ===
{| class="wikitable"
!Long COVID
!Post-acute SARS
!ME/CFS
!POTS
!MCAS
|-
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|-
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|}

== See also ==
* [[Long COVID]]

Long COVID pathophysiology

2021-08-11T14:10:48Z

JenB:

Infection and immunity

Neurological and neuropsychiatric

Cardiovascular

== Comparison to other conditions ==

=== Post-acute SARS ===
ME/CFS

POTS

MCAS

Alzheimer’s

Traumatic Brain Injury
{| class="wikitable"
!Long COVID
!Post-acute SARS
!ME/CFS
!POTS
!MCAS
|-
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== See also ==
* [[Long COVID]]

Long COVID pathophysiology

2021-08-11T14:03:43Z

JenB:Created page

Long COVID

2021-08-11T14:01:51Z

JenB:Linked to new page focused on long COVID pathophysiology

[[File:Long-COVID.jpg|alt=Long COVID logo with Coronavirus icon |thumb]]
'''Long COVID''', '''long tail covid''', '''Post-Acute Sequelae of COVID-19''' '''(PASC)''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.<ref name="Navabi2020">{{Cite journal|title=Long covid: How to define it and how to manage it|last=Nabavi|first=Nikki|url=https://www.bmj.com/content/370/bmj.m3489|date=Sep 7, 2020|journal=The BMJ|volume=370|pages=bmj.m3489}}</ref><ref name="BMJ11Aug2020" /><ref name="long-haulers-redefining">{{Cite news|url=https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/|title=Long-Haulers Are Redefining COVID-19|last=Yong|first=Ed|date=Aug 19, 2020|work=The Atlantic|access-date=2020-08-21|archive-url=|archive-date=|url-status=|issn=1072-7825|quote=|author-link=}}</ref><ref name="NIHR.ac.uk15Oct2020">{{Cite web|url=https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891|title=Living with COVID: NIHR publishes dynamic themed review into ‘ongoing COVID’|last=National Institute for Health Research|first=|authorlink=|date=|website=www.nihr.ac.uk|archive-url=|archive-date=|url-status=|access-date=2020-10-15}}</ref>

The name '''Long COVID''' was coined by patient [[Elisa Perego]] in May 2020,<ref name="BMJ1Oct2020" /> and in February 2021 the [[Centers for Disease Control|CDC]] introduced the alternative name '''Post-Acute Sequelae of COVID-19''' (PASC).<ref name="PASC-blog">{{Cite web|url=https://directorsblog.nih.gov/tag/post-acute-sequelae-of-covid-19|title =
Trying to Make Sense of Long COVID Syndrome
|date =Jan 19, 2021|first= Francis|last = Collins|author-link =Francis Collins |access-date =Mar 1, 2021}}</ref>

In February 2020, the [[World Health Organization]] stated that the expected recovery time from [[COVID-19]] was 2 weeks for mild cases, and between three and six weeks for severe cases;<ref name="WHOFeb2020">{{Cite web|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020|title=WHO Director-General's opening remarks at the media briefing on COVID-19|last=World Health Organization|first=|authorlink=World Health Organization|date=Feb 24, 2020|website=[[World Health Organization]]|language=en|archive-url=|archive-date=|url-status=|access-date=2020-09-24}}</ref> follow-up studies then identified a significant number of COVID-19 patients had remained ill much longer than this: those with long COVID.<ref name="Navabi2020" /><ref name="BMJ11Aug2020" />

A similar phenomenon to long COVID occurred after the 2003 outbreak of the similar SARS coronavirus, which lead to a [[Severe acute respiratory syndrome#post-SARS|post-SARS syndrome]] being proposed that included chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep. Another study found a subgroup SARS survivors developed [[chronic fatigue syndrome]] immediately after SARS.<ref name="Moldofsky2011">{{Cite journal|last=Moldofsky|first=Harvey|last2=Patcai|first2=John|date=2011-03-24|title=Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study|url=https://doi.org/10.1186/1471-2377-11-37|journal=BMC Neurology|volume=11|issue=1|pages=37|doi=10.1186/1471-2377-11-37|issn=1471-2377|pmc = 3071317|pmid=21435231}}</ref>
<ref name="Lam2009">{{Cite journal|last=Lam|first=Marco Ho-Bun|last2=Wing|first2=Yun-Kwok|last3=Yu|first3=Mandy Wai-Man|last4=Leung|first4=Chi-Ming|last5=Ma|first5=Ronald C. W.|last6=Kong|first6=Alice P. S.|last7=So|first7=W. Y.|last8=Fong|first8=Samson Yat-Yuk|last9=Lam|first9=Siu-Ping|date=2009-12-14|title=Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors: Long-term Follow-up|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378|journal=Archives of Internal Medicine|language=en|volume=169|issue=22|pages=2142–2147|doi=10.1001/archinternmed.2009.384|issn=0003-9926}}</ref>

==Long-haulers==
A "long-hauler" is someone with long COVID, meaning someone who became ill with confirmed or suspected [[COVID-19]], who has remained ill with long-term symptoms many weeks or months later after first becoming ill.<ref name="long-haulers-redefining" /><ref name="BMJ1Oct2020">{{Cite web|url=https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/|title=Why we need to keep using the patient made term “Long Covid”|date=2020-10-01|last=Perego|first =Elisa |author-link =Elisa Perego|last2 =Callard|first2=Felicity|authorlink2=Felicity Callard|last3=Stras|first3=Laurie|authorlink3=Laurie Stras|last4=Melville-Jóhannesson|first4=Barbara|authorlink4=Barbara Melville-Jóhannesson|last5=Pope|first5=Rachel |authorlink5=Rachel Pope|last6=Alwan|first6=
Nisreen A|authorlink6=Nisreen Alwan|website=The BMJ|language=en-US|access-date=2020-10-11}}</ref>

==What is long COVID==
[[File:Long-COVID-1in10.jpg|alt=Long COVID poster - 1 in 10 people with COVID-19 may develop long COVID|thumb]]
Long COVID appears to be a multisystem disease, and may occur after any severity of COVID-19, including after relatively mild cases.<ref name="BMJ11Aug2020" /><ref name="BMJ1Oct2020" />

=== Four different syndromes ===
A recent review suggested that long COVID may actually be four different syndromes:
* [[Post-COVID-19 illness#pics|Post-Intensive Care Syndrome]]
* [[Postviral fatigue syndrome|Postviral Fatigue Syndrome]] (ME/CFS)
* Long Term COVID Syndrome
* Permanent organ damage
Patients with long COVID may have several syndromes at once.<ref name="NIHR15Oct2020" />

=== Signs and symptoms ===
Patient surveys have reported that the following symptoms commonly occur in long COVID.
*[[Fatigue]], which may be extreme (profound)
*[[myalgia|Muscle pain]] or body aches
*[[dyspnea|Breathlessness]]
*[[Concentration problems]]
*Inability to [[exercise]]/[[exercise intolerance]]
*[[Headache]]
*[[Insomnia]] or [[sleep dysfunction|problems sleeping]]
*Heavy chest, a feeling of pressure on the chest, or chest pain
Other reported symptoms include:
*[[Anxiety]]
*[[Paresis|Muscle weakness]]
*[[Memory problems]]
*Skin rashes
*[[Sore throat]] and difficulty swallowing
*[[Heart palpitation]]s
*[[Fever]]
*[[Diarrhea]]
*[[Dizziness]]
*The sensation of [[pins and needles]]
*Cough
*[[Low-grade fever]]
*Loss of sense of taste and smell
*[[Joint pain]]
*New onset diabetes<ref name="Rubino2020">{{Cite journal|last=Rubino|first=Francesco|last2=Amiel|first2=Stephanie A.|last3=Zimmet|first3=Paul|last4=Alberti|first4=George|last5=Bornstein|first5=Stefan|last6=Eckel|first6=Robert H.|last7=Mingrone|first7=Geltrude|last8=Boehm|first8=Bernhard|last9=Cooper|first9=Mark E.|date=2020-08-20|title=New-Onset Diabetes in Covid-19|url=https://doi.org/10.1056/NEJMc2018688|journal=New England Journal of Medicine|volume=383|issue=8|pages=789–790|doi=10.1056/NEJMc2018688|issn=0028-4793|pmc = 7304415|pmid=32530585}}</ref>
*New onset [[Hypertension|high blood pressure]]<ref name="Lambert25Jul2020" /><ref name="Navabi2020" /><ref name="NHSlongSep2020">{{Cite web|url=https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects|title=COVID-19 Long Term Health Effects|last=National Health Service|first=|authorlink=National Health Service|last2=|first2=|authorlink2=|date=Sep 7, 2020|website=|archive-url=|archive-date=|url-status=|access-date=}}</ref><ref name="Yellin2020" />

{{Quote box|“A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back|source=Dr. Nisreen Alwan, BMJ, Sep 2020}}

== COVID-19 testing ==
While some people with long COVID did have a positive test result for COVID-19, others were denied tests due to the limited availability of tests at the time, or they tested negative but were found to have clear evidence of COVID-19 from blood count tests or chest X-rays.<ref name="NIHR15Oct2020">{{Cite web|url=https://evidence.nihr.ac.uk/themedreview/living-with-covid19|title=Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid).|last=NIHR|first=|authorlink=|last2=|first2=|authorlink2=|date=October 2020|website=evidence.nihr.ac.uk|language=en-GB|archive-url=|archive-date=|url-status=|access-date=2020-10-15}}</ref><ref name="Kingstone2020" /> Some people with Long COVID have described never having a cough or fever at the start of their illness, but developed these symptoms later. Long COVID diagnosis does not depend on a previous positive test.<ref name="NIHR15Oct2020" /><ref name="Kingstone2020" />

==Clinical findings ==

There is no blood test or diagnostic biomarker to identify patients with long COVID. A study in the UK found that just over 10% of long COVID patients had abnormal findings on the standard tests and did not find an association between standard test results and degree of organ damage or long COVID severity.<ref name="Dennis2020" /> The same study used MRI scans combined with patient questionnaires to assess organ damage, finding that multi-organ impairment was common in people with long COVID, despite the fact that 80% had not been hospitalized for [[COVID-19]], the average patient age was forty-four years old, and rates of pre-existing conditions were also low.<ref name="Dennis2020" />

==Research findings ==
{{Main article|page_name=Long COVID pathophysiology}}

Surveys of data collected and published by long haulers using social media were the first evidence of what symptoms and health problems were caused by long COVID.<ref name="bodypoliticMay2020" /> Later academic studies confirmed many of the initial long hauler survey findings, although many only involved patients discharged from hospital,<ref name="Puntmann2020" /> patients who had been able to access early testing and tested positive, or patients who had sought medical care in a particular location.<ref name="Arnold2020b" /> People with mild COVID-19 symptoms, leaving people denied testing and those who may have had false negative test results and people who tested positive but were asymptomatic underrepresented in long COVID research.<ref name="bodypoliticMay2020" />

==Treatment==

===Pacing===
Pacing is a method of activity management which aims to adapt everday activities in order to avoid relapses or increased symptoms.
{{See also|Pacing}}

===Exercise therapy ===
ME/CFS patient groups have raised concerns about the use of [[graded exercise therapy]] (GET) in long COVID patients and a similar warning has been issued by [[NICE]] in the [[United Kingdom|UK]].<ref name="GETcovidForwardME" /> Graded exercise therapy, which is sometimes incorrectly referred to as "activity management" involves patients initially reducing their activity levels to a level that prevents regular crashes, and then typically increasing activity by 10% each week regardless of any increased symptoms or worsening illness. In graded exercise patients are told to ignore deterioration or increased symptoms and "push through" them.

====Theory and evidence ====
In graded exercise therapy patients are told that their symptoms are caused only by [[deconditioning|inactivity]] and other "bad habits" rather than an underlying illness. These assumptions have very weak evidence, and significant evidence exists of underlying illness in ME/CFS; there is a lack of research about exercise therapy for long COVID illness<ref name="Navabi2020" /> but some symptoms are inconsistent with this "deconditioning" assumption and some research has found physical abnormalities in some patients weeks or month after infection. Surveys of ME/CFS patients have consistently shown that large numbers of patients deteriorate as a result of graded exercise therapy, and a significant number become severely ill and never return to the level of functioning they had before the treatment.

==ME/CFS==
[[Postviral fatigue syndrome]] is one of the previous names used for [[Myalgic Encephalomyelitis]] (ME), sometimes known as [[Chronic fatigue syndrome|Chronic Fatigue Syndrome]] (CFS), and it commonly begins immediately after events such as a virus, bacterial or other infection.<ref name="ICC2011primer">{{citation
| last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers
| last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande
| last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick
| last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell
| last7 = Staines | first7 = D | authorlink7 = Donald Staines
| last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles
| last9 = Speight | first9 = N | authorlink9 = Nigel Speight
| last10 = Vallings | first10= R | authorlink10= Rosamund Vallings
| last11 = Bateman | first11= L | authorlink11= Lucinda Bateman
| last12 = Bell | first12= DS | authorlink12= David Bell
| last13 = Carlo-Stella | first13= N | authorlink13= Nicoletta Carlo-Stella
| last14 = Chia | first14= J | authorlink14= John Chia
| last15 = Darragh | first15= A | authorlink15= Austin Darragh
| last16 = Gerken | first16= A | authorlink16= Anne Gerken
| last17 = Jo | first17= D | authorlink17= Daehyun Jo
| last18 = Lewis | first18= DP | authorlink18= Donald Lewis
| last19 = Light | first19= AR | authorlink19= Alan Light
| last20 = Light | first20= KC | authorlink20= Kathleen Light
| last21 = Marshall-Gradisnik | first21= S | authorlink21= Sonya Marshall-Gradisnik
| last22 = McLaren-Howard | first22= J | authorlink22= John McLaren-Howard| last23 = Mena | first23= I | authorlink23= Ismael Mena
| last24 = Miwa | first24= K | authorlink24= Kunihisa Miwa
| last25 = Murovska | first25= M | authorlink25= Modra Murovska
| last26 = Stevens | first26= SR | authorlink26= Staci Stevens
| title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners
| date = 2012| isbn = 978-0-9739335-3-6| url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf
}}</ref> ME has been a sequela of over [[Epidemic myalgic encephalomyelitis|one hundred outbreaks]], in addition to sporadic infections. ME/CFS is not normally diagnosed until symptoms have persisted for six months or more, and tests must be run to exclude other possible causes of the symptoms.<ref name="SEID2015">{{Citation|last=Institute of Medicine|author-link=Institute of Medicine|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|location=Washington, DC|publisher=The National Academies Press|date=2015|url=https://www.ncbi.nlm.nih.gov/books/NBK284902/}}</ref> Some contagious diseases including [[Epstein-Barr virus]], certain [[enterovirus]]es,<ref name="ICC2011primer" /> and the [[Severe acute respiratory syndrome|SARS]] coronavirus,<ref name="Moldofsky2011" /> have caused outbreaks of ME/CFS. It is not yet known how likely it is for ME/CFS to begin immediately after COVID-19 illness, although around 10% people with certain viruses are known to develop ME/CFS, and according to [[the BMJ]] around 10% of people with COVID-19 have developed long COVID. A significant number of those with long COVID have been found to develop ME/CFS, but it is not known how common this is.<ref name="BMJ11Aug2020" /><ref name="NIHR15Oct2020" />

==Patient surveys ==
'''Not peer reviewed'''
* May 2020, [https://patientresearchcovid19.com/research/report-1/ What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team]<ref name="bodypoliticMay2020">{{Cite web|url=https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic|title=What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team|date=May 11, 2020|vauthors=Assaf G, Davis H, McCorkell L, Wei H, O'Neil B, Akrami A, Low R, Mercier J, A A, L T, C A, S M, N L, H N, D JD, S}}</ref> - by [[Body Politic|Body Politic and Patient Led Research Collaborative]]
::Data collected: Apr 21 - May 2 2020. Respondents: 640

* Jul 2020, [https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf COVID-19 “Long Hauler” Symptoms Survey Report]<ref name="Lambert25Jul2020">{{Cite web|url=https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf|title=COVID-19 “Long Hauler” Symptoms Survey Report|last=Lambert|first=Natalie J|author-link=Natalie Lambert|last2=Survivor Corps|author-link2=Survivor Corps|publisher=Indiana University School of Medicine|date=Jul 2020}}</ref> - with Survivor Corps
::Data collected: Jul 25, 2020. Respondents: 1,567+
::
:* Dec 2020, [https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2 Charactering Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact] - by [https://patientresearchcovid19.com/ Body Politic and Patient Led Research Collaborative]
:** Respondents: 3,762+

==Notable studies==
*Jul 24, 2020, Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)<ref name="Puntmann2020">{{Cite journal|last=Puntmann|first=Valentina O.|last2=Carerj|first2=M. Ludovica|last3=Wieters|first3=Imke|last4=Fahim|first4=Masia|last5=Arendt|first5=Christophe|last6=Hoffmann|first6=Jedrzej|last7=Shchendrygina|first7=Anastasia|last8=Escher|first8=Felicitas|last9=Vasa-Nicotera|first9=Mariuca|date=2020-07-27|title=Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)|url=https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916|journal=JAMA Cardiology|language=en|doi=10.1001/jamacardio.2020.3557|issn=2380-6583}}</ref> - [https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 (Full text)]
*Aug 11, 2020, Management of post-acute covid-19 in primary care<ref name="BMJ11Aug2020">{{cite journal|title=Management of post-acute covid-19 in primary care|last=Greenhalgh|first=Trisha|author-link =Trisha Greenhalgh|first2=Matthew|last2=Knight|author-link2=Matthew Knight|author-link3=Christine A'Court|first3=Christine|last3=A'Court|first4=Maria|last4=Buxton|first5= Laiba|last5=Husain|journal=The BMJ|date=Aug 11, 2020|volume=370|doi=10.1136/bmj.m3026|pages=m3026|url =https://doi.org/10.1136/bmj.m3026}}</ref> - [https://doi.org/10.1136/bmj.m3026 (Full text)]
*Aug 20, 2020, New-Onset Diabetes in Covid-19<ref name="Rubino2020" /> - [https://www.nejm.org/doi/full/10.1056/NEJMc2018688 (Full text)]
*Oct 1, 2020, Long-term consequences of COVID-19: research needs<ref name="Yellin2020">{{Cite journal|last=Yelin|first=Dana|last2=Wirtheim|first2=Eytan|last3=Vetter|first3=Pauline|last4=Kalil|first4=Andre C.|last5=Bruchfeld|first5=Judith|last6=Runold|first6=Michael|last7=Guaraldi|first7=Giovanni|last8=Mussini|first8=Cristina|last9=Gudiol|first9=Carlota|date=2020-10-01|title=Long-term consequences of COVID-19: research needs|url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/abstract|journal=The Lancet Infectious Diseases|language=English|volume=20|issue=10|pages=1115–1117|doi=10.1016/S1473-3099(20)30701-5|issn=1473-3099|pmid=32888409}}</ref> - [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext (Full text)]
*Oct 14, 2020, Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID<ref name="Kingstone2020">{{Cite journal|last=Kingstone|first=Tom|author-link=|last2=Taylor|first2=Anna K.|author-link2=|last3=O'Donnell|first3=Catherine A.|author-link3=|last4=Atherton|first4=Helen|author-link4=|last5=Blane|first5=David N.|author-link5=|last6=Chew-Graham|first6=Carolyn A.|author-link6=Carolyn Chew-Graham|date=2020-10-14|title=Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID|url=https://bjgpopen.org/content/early/2020/10/12/bjgpopen20X101143|journal=BJGP Open|language=en|volume=|issue=|pages=|doi=10.3399/bjgpopen20X101143|issn=2398-3795|pmc=|pmid=33051223|access-date=|quote=|via=}}</ref> - [https://bjgpopen.org/content/bjgpoa/early/2020/10/12/bjgpopen20X101143.full.pdf (Full text)]
*Oct 16, 2020, Multi-organ impairment in low-risk individuals with long COVID<ref name="Dennis2020">{{Cite journal|last=Dennis|first=Andrea|author-link=|last2=Wamil|first2=Malgorzata|author-link2=|last3=Kapur|first3=Sandeep|author-link3=|last4=Alberts|first4=Johann|author-link4=|last5=Badley|first5=Andrew D.|author-link5=|last6=Decker|first6=Gustav Anton|author-link6=|last7=Rizza|first7=Stacey A.|last8=Banerjee|first8=Rajarshi|last9=Banerjee|first9=Amitava|author-link9=Amitava Banerjee|date=2020-10-16|title=Multi-organ impairment in low-risk individuals with long COVID|url=https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.14.20212555|doi=10.1101/2020.10.14.20212555|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.1101/2020.10.14.20212555 (Full text)]
*Oct 21, 2020, Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App<ref name="Sudre2020a">{{Cite journal|last=Sudre|first=Carole H.|author-link=|last2=Murray|first2=Benjamin|author-link2=|last3=Varsavsky|first3=Thomas|author-link3=|last4=Graham|first4=Mark S.|author-link4=|last5=Penfold|first5=Rose S.|author-link5=|last6=Bowyer|first6=Ruth C.|author-link6=|last7=Pujol|first7=Joan Capdevila|last8=Klaser|first8=Kerstin|last9=Antonelli|first9=Michela|date=2020-10-19|others=|title=Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App|url=https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.19.20214494|doi=10.1101/2020.10.19.20214494|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1.full-text (Full text)]
*Dec 2020 (pre-print) / Jul 15, 2021, Characterizing long COVID in an international cohort: 7 months of symptoms and their impact<ref name="Davis2021a">{{Cite journal|last=Davis|first=Hannah E.|last2=Assaf|first2=Gina S.|last3=McCorkell|first3=Lisa|last4=Wei|first4=Hannah|last5=Low|first5=Ryan J.|last6=Re'em|first6=Yochai|last7=Redfield|first7=Signe|last8=Austin|first8=Jared P.|last9=Akrami|first9=Athena|date=2021-07-15|title=Characterizing long COVID in an international cohort: 7 months of symptoms and their impact|url=https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/abstract|journal=EClinicalMedicine|language=English|volume=0|issue=0|doi=10.1016/j.eclinm.2021.101019|issn=2589-5370}}</ref> - [https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/abstract (Abstract)]
*Dec 20, 2020, Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort<ref name="Arnold2020b">{{Cite journal|last=Arnold|first=David T.|author-link=David Arnold|last2=Hamilton|first2=Fergus W.|last3=Milne|first3=Alice|last4=Morley|first4=Anna J.|last5=Viner|first5=Jason|last6=Attwood|first6=Marie|last7=Noel|first7=Alan|last8=Gunning|first8=Samuel|last9=Hatrick|first9=Jessica|date=2021-04-01|title=Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort|url=https://thorax.bmj.com/content/76/4/399|journal=Thorax|language=en|volume=76|issue=4|pages=399–401|doi=10.1136/thoraxjnl-2020-216086|issn=0040-6376|pmid=33273026}}</ref> - [https://thorax.bmj.com/content/76/4/399 (Full text)] - from the DISCOVER project
*Jan 18, 2021, Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome?<ref name="Komaroff2021a">{{Cite journal|last=Komaroff|first=Anthony L.|author-link=Anthony Komaroff|last2=Bateman|first2=Lucinda|author-link2=Lucinda Bateman|date=2021|title=Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?|url=https://www.frontiersin.org/articles/10.3389/fmed.2020.606824/full?s=03|journal=Frontiers in Medicine|language=English|volume=|issue=|pages=|doi=10.3389/fmed.2020.606824|issn=2296-858X|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.frontiersin.org/articles/10.3389/fmed.2020.606824/full?s=03 (Full text)]
*Mar 27, 2021, COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection<ref name="Lambert2021a">{{Cite journal|last=Lambert|first=Natalie|author-link=Natalie Lambert|last2=Corps|first2=Survivor|author-link2=Survivor Corps|last3=El-Azab|first3=Sarah A.|author-link3=|last4=Ramrakhiani|first4=Nathan S.|author-link4=|last5=Barisano|first5=Anthony|author-link5=|last6=Yu|first6=Lu|author-link6=|last7=Taylor|first7=Kaitlyn|last8=Esperanca|first8=Alvaro|last9=Downs|first9=Charles A.|date=2021-03-27|title=COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection|url=https://www.medrxiv.org/content/10.1101/2021.03.22.21254026v2|journal=medRxiv|language=en|volume=|issue=|pages=2021.03.22.21254026|doi=10.1101/2021.03.22.21254026|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.1101/2021.03.22.21254026 (Full text)]
*May 11, 2021, Mayo Clinic Proceedings: Post COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at the Mayo Clinic and Characteristics of the Initial Patient Cohort<ref name="mayo2021a">{{Cite journal|last=Vanichkachorn|first=Greg|last2=Newcomb|first2=Richard|last3=Cowl|first3=Clayton T.|last4=Murad|first4=M. Hassan|last5=Breeher|first5=Laura|last6=Miller|first6=Sara|last7=Trenary|first7=Michael|last8=Neveau|first8=Daniel|last9=Higgins|first9=Steven|date=2021-07-01|title=Post–COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at Mayo Clinic and Characteristics of the Initial Patient Cohort|url=https://www.mayoclinicproceedings.org/article/S0025-6196(21)00356-6/abstract|journal=Mayo Clinic Proceedings|language=English|volume=96|issue=7|pages=1782–1791|doi=10.1016/j.mayocp.2021.04.024|issn=0025-6196|pmid=34218857}}</ref> - [https://www.mayoclinicproceedings.org/article/S0025-6196(21)00356-6/abstract (Abstract)]
*Jun 7, 2021, Insights from ME/CFS May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome<ref name="Komaroff2021b">{{Cite journal|last=Komaroff|first=Anthony L.|author-link=Anthony Komaroff|last2=Lipkin|first2=W. Ian|author-link2=Ian Lipkin|date=2021-06-07|title=Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome|url=https://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(21)00134-9|journal=Trends in Molecular Medicine|language=English|volume=|issue=|pages=|doi=10.1016/j.molmed.2021.06.002|issn=1471-4914|pmc=|pmid=34175230|access-date=|quote=|via=}}</ref> - [https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(21)00134-9 (Full text)]
*Jun 23, 2021, Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms<ref name="Proal2021">https://doi.org/10.3389/fmicb.2021.698169</ref> - [https://doi.org/10.1101/2020.12.24.20248802 (Full text)]

==Articles and editorials ==
*Jun 15, 2021, White Paper: A Detailed Study of Patients with Long-Haul COVID<ref name="Fairthealth2021">{{Cite web|url=https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf|publisher=FAIR Health|date=Jun 18, 2020|title=A Detailed Study of Patients with Long-Haul COVID: An Analysis of Private Healthcare Claims. A FAIR Health White Paper}}</ref> [https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf (Full text)]
*Jun 24, 2021, Covid-19: Third of people infected have long term symptoms<ref name="ODowd2021">{{Cite journal|last=O’Dowd|first=Adrian|date=2021-06-24|title=Covid-19: Third of people infected have long term symptoms|url=https://www.bmj.com/content/373/bmj.n1626|journal=BMJ|language=en|volume=373|pages=n1626|doi=10.1136/bmj.n1626|issn=1756-1833|pmid=34168002}}</ref> [https://www.bmj.com/content/373/bmj.n1626 (Editorial)]

==Presentations, interviews and videos==
*Aug 2020, [https://solvecfs.org/wp-content/uploads/2020/08/Post-COVID%20ME-to%20Solve.pdf Will Covid-19 lead to ME/CFS in some people?] - presentation - Dr [[Anthony Komaroff]]
*Jul 2020, [https://www.youtube.com/watch?v=IIeOoS_A4c8 Message in a Bottle] video - [[LongCovidSOS]]
*Jun 2020, [https://www.biomax.com/lib/press-releases/Initial-Result-Announcment_English.pdf Health of Corona Patients at Home in Alarmingly Poor Health Even After Several Months - Dutch Lung Foundation] - Press release (English translation) - [https://www.ad.nl/binnenland/longfonds-gezondheid-thuiszittende-coronapatienten-schrikbarend-slecht~a45346fe/ Dutch]

==Letters and blogs==
*May 2020, [http://somatosphere.net/2020/mild-covid.html/ Very, very mild: Covid-19 symptoms and illness classification] - [[Felicity Callard]]
*Jul 2020, [https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf Letter re Covid-19 Management and Exercise Caution]<ref name="GETcovidForwardME">{{Cite web|url=https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf|date=2020-08-27|last=Forward-ME|author-link=Forward-ME|title =Letter re Covid-19 Management and Exercise Caution}}</ref> - [[Forward-ME]]
*Sep 2020, [https://mecfsresearchreview.me/2020/09/17/understanding-long-covid-a-shortcut-to-solving-me-cfs/?#symptoms Understanding Long Covid, A Shortcut to Solving ME/CFS?] - [[Simon McGrath]]
*Sep 2020, [https://wellcomeopenresearch.org/articles/5-224 Why the Patient-Made Term 'Long Covid' is needed] - Open Letter
*Oct 2020, [https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/ Why we need to keep using the patient made term “Long Covid”] - [[The BMJ]]
*January 2021, [https://directorsblog.nih.gov/tag/post-acute-sequelae-of-covid-19/ Trying to Make Sense of Long COVID Syndrome] - Dr. Francis Collins, CDC director

==National and international health bodies==
*[https://doi.org/10.1136/bmj.m2912 NICE cautions against using graded exercise therapy for patients recovering from COVID-19]<ref name="NICEcautionBMJ">{{Cite journal|last=Torjesen|first=Ingrid|date=2020-07-21|title=NICE cautions against using graded exercise therapy for patients recovering from covid-19|url=https://www.bmj.com/content/370/bmj.m2912|journal=The BMJ|language=en|volume=370|doi=10.1136/bmj.m2912|issn=1756-1833|pmid=32694164}}</ref>

==News articles ==
* Oct 2020, [https://www.theguardian.com/world/2020/oct/21/women-aged-50-60-at-greatest-risk-of-long-covid-experts-suggest Women aged 50-60 at greatest risk of ‘long Covid’, experts suggest] - The Guardian

* Oct 2020, [https://www.wsj.com/articles/these-doctors-have-long-term-covid-now-theyre-pushing-for-better-care-11603144474 These Doctors Have Long-Term Covid. Now They’re Pushing for Better Care.] - Wall Street Journal
* Oct 2020, [https://time.com/5897992/long-haul-coronavirus-me-cfs/ Have We Been Thinking About Long-Haul Coronavirus All Wrong?] - Time
* Oct 2020, [https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891 Living with COVID: NIHR publishes dynamic-themed review into 'ongoing COVID'] - National Institute of Health Research
* Oct 2020, [https://www.theguardian.com/world/2020/oct/04/long-covid-the-evidence-of-lingering-heart-damage Long Covid: the evidence of lingering heart damage] - The Observer
* Sep 2020, [https://www.bbc.co.uk/news/uk-england-leicestershire-54106073 Coronavirus patient unable to work six months on] - BBC News
* Aug 2020, [https://www.huffingtonpost.co.uk/entry/long-term-symptoms-of-covid-19-identified-in-study-of-hospital-patients_uk_5f2bc0f6c5b64d7a55eefcfa The Most Common Long-Term Symptoms Of Covid-19] - HuffPost UK
* Jul 2020, [https://www.sciencemag.org/news/2020/07/brain-fog-heart-damage-covid-19-s-lingering-problems-alarm-scientists From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists] - Science Mag

==See also==
*[[List of famous people with long COVID]]
*[[List of open letters about long COVID]]
*[[Post-COVID-19 illness]]
*[[COVID-19]] coronavirus disease 19
*[[Myalgic encephalomyelitis|Myalgic encephalomyelitis and chronic fatigue syndrome]]
*[[Postviral fatigue syndrome]]
*[[Post-Ebola syndrome]]
*[[Encephalitis lethargica]]
*[[Paul Garner]]
*[[Nisreen Alwan]]

==Learn more==
*[https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects COVID-19 Long Term Health Effects]
*[https://www.bmj.com/sites/default/files/infographics/1353078336/static-infographic/background.png Infographic: "Long covid" in primary care] - BMJ journal
* List of long COVID studies (draft) - [[MEAction|#MEAction]]

==References==
{{reflist}}

[[Category:Potential comorbidities]]
[[Category:Diagnoses]]
[[Category:Long COVID]]

Long COVID

2021-08-11T13:55:25Z

JenB:Linked ME, CFS, and epidemic ME pages

[[File:Long-COVID.jpg|alt=Long COVID logo with Coronavirus icon |thumb]]
'''Long COVID''', '''long tail covid''', '''Post-Acute Sequelae of COVID-19''' '''(PASC)''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.<ref name="Navabi2020">{{Cite journal|title=Long covid: How to define it and how to manage it|last=Nabavi|first=Nikki|url=https://www.bmj.com/content/370/bmj.m3489|date=Sep 7, 2020|journal=The BMJ|volume=370|pages=bmj.m3489}}</ref><ref name="BMJ11Aug2020" /><ref name="long-haulers-redefining">{{Cite news|url=https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/|title=Long-Haulers Are Redefining COVID-19|last=Yong|first=Ed|date=Aug 19, 2020|work=The Atlantic|access-date=2020-08-21|archive-url=|archive-date=|url-status=|issn=1072-7825|quote=|author-link=}}</ref><ref name="NIHR.ac.uk15Oct2020">{{Cite web|url=https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891|title=Living with COVID: NIHR publishes dynamic themed review into ‘ongoing COVID’|last=National Institute for Health Research|first=|authorlink=|date=|website=www.nihr.ac.uk|archive-url=|archive-date=|url-status=|access-date=2020-10-15}}</ref>

The name '''Long COVID''' was coined by patient [[Elisa Perego]] in May 2020,<ref name="BMJ1Oct2020" /> and in February 2021 the [[Centers for Disease Control|CDC]] introduced the alternative name '''Post-Acute Sequelae of COVID-19''' (PASC).<ref name="PASC-blog">{{Cite web|url=https://directorsblog.nih.gov/tag/post-acute-sequelae-of-covid-19|title =
Trying to Make Sense of Long COVID Syndrome
|date =Jan 19, 2021|first= Francis|last = Collins|author-link =Francis Collins |access-date =Mar 1, 2021}}</ref>

In February 2020, the [[World Health Organization]] stated that the expected recovery time from [[COVID-19]] was 2 weeks for mild cases, and between three and six weeks for severe cases;<ref name="WHOFeb2020">{{Cite web|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020|title=WHO Director-General's opening remarks at the media briefing on COVID-19|last=World Health Organization|first=|authorlink=World Health Organization|date=Feb 24, 2020|website=[[World Health Organization]]|language=en|archive-url=|archive-date=|url-status=|access-date=2020-09-24}}</ref> follow-up studies then identified a significant number of COVID-19 patients had remained ill much longer than this: those with long COVID.<ref name="Navabi2020" /><ref name="BMJ11Aug2020" />

A similar phenomenon to long COVID occurred after the 2003 outbreak of the similar SARS coronavirus, which lead to a [[Severe acute respiratory syndrome#post-SARS|post-SARS syndrome]] being proposed that included chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep. Another study found a subgroup SARS survivors developed [[chronic fatigue syndrome]] immediately after SARS.<ref name="Moldofsky2011">{{Cite journal|last=Moldofsky|first=Harvey|last2=Patcai|first2=John|date=2011-03-24|title=Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study|url=https://doi.org/10.1186/1471-2377-11-37|journal=BMC Neurology|volume=11|issue=1|pages=37|doi=10.1186/1471-2377-11-37|issn=1471-2377|pmc = 3071317|pmid=21435231}}</ref>
<ref name="Lam2009">{{Cite journal|last=Lam|first=Marco Ho-Bun|last2=Wing|first2=Yun-Kwok|last3=Yu|first3=Mandy Wai-Man|last4=Leung|first4=Chi-Ming|last5=Ma|first5=Ronald C. W.|last6=Kong|first6=Alice P. S.|last7=So|first7=W. Y.|last8=Fong|first8=Samson Yat-Yuk|last9=Lam|first9=Siu-Ping|date=2009-12-14|title=Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors: Long-term Follow-up|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378|journal=Archives of Internal Medicine|language=en|volume=169|issue=22|pages=2142–2147|doi=10.1001/archinternmed.2009.384|issn=0003-9926}}</ref>

==Long-haulers==
A "long-hauler" is someone with long COVID, meaning someone who became ill with confirmed or suspected [[COVID-19]], who has remained ill with long-term symptoms many weeks or months later after first becoming ill.<ref name="long-haulers-redefining" /><ref name="BMJ1Oct2020">{{Cite web|url=https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/|title=Why we need to keep using the patient made term “Long Covid”|date=2020-10-01|last=Perego|first =Elisa |author-link =Elisa Perego|last2 =Callard|first2=Felicity|authorlink2=Felicity Callard|last3=Stras|first3=Laurie|authorlink3=Laurie Stras|last4=Melville-Jóhannesson|first4=Barbara|authorlink4=Barbara Melville-Jóhannesson|last5=Pope|first5=Rachel |authorlink5=Rachel Pope|last6=Alwan|first6=
Nisreen A|authorlink6=Nisreen Alwan|website=The BMJ|language=en-US|access-date=2020-10-11}}</ref>

==What is long COVID==
[[File:Long-COVID-1in10.jpg|alt=Long COVID poster - 1 in 10 people with COVID-19 may develop long COVID|thumb]]
Long COVID appears to be a multisystem disease, and may occur after any severity of COVID-19, including after relatively mild cases.<ref name="BMJ11Aug2020" /><ref name="BMJ1Oct2020" />

=== Four different syndromes ===
A recent review suggested that long COVID may actually be four different syndromes:
* [[Post-COVID-19 illness#pics|Post-Intensive Care Syndrome]]
* [[Postviral fatigue syndrome|Postviral Fatigue Syndrome]] (ME/CFS)
* Long Term COVID Syndrome
* Permanent organ damage
Patients with long COVID may have several syndromes at once.<ref name="NIHR15Oct2020" />

=== Signs and symptoms ===
Patient surveys have reported that the following symptoms commonly occur in long COVID.
*[[Fatigue]], which may be extreme (profound)
*[[myalgia|Muscle pain]] or body aches
*[[dyspnea|Breathlessness]]
*[[Concentration problems]]
*Inability to [[exercise]]/[[exercise intolerance]]
*[[Headache]]
*[[Insomnia]] or [[sleep dysfunction|problems sleeping]]
*Heavy chest, a feeling of pressure on the chest, or chest pain
Other reported symptoms include:
*[[Anxiety]]
*[[Paresis|Muscle weakness]]
*[[Memory problems]]
*Skin rashes
*[[Sore throat]] and difficulty swallowing
*[[Heart palpitation]]s
*[[Fever]]
*[[Diarrhea]]
*[[Dizziness]]
*The sensation of [[pins and needles]]
*Cough
*[[Low-grade fever]]
*Loss of sense of taste and smell
*[[Joint pain]]
*New onset diabetes<ref name="Rubino2020">{{Cite journal|last=Rubino|first=Francesco|last2=Amiel|first2=Stephanie A.|last3=Zimmet|first3=Paul|last4=Alberti|first4=George|last5=Bornstein|first5=Stefan|last6=Eckel|first6=Robert H.|last7=Mingrone|first7=Geltrude|last8=Boehm|first8=Bernhard|last9=Cooper|first9=Mark E.|date=2020-08-20|title=New-Onset Diabetes in Covid-19|url=https://doi.org/10.1056/NEJMc2018688|journal=New England Journal of Medicine|volume=383|issue=8|pages=789–790|doi=10.1056/NEJMc2018688|issn=0028-4793|pmc = 7304415|pmid=32530585}}</ref>
*New onset [[Hypertension|high blood pressure]]<ref name="Lambert25Jul2020" /><ref name="Navabi2020" /><ref name="NHSlongSep2020">{{Cite web|url=https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects|title=COVID-19 Long Term Health Effects|last=National Health Service|first=|authorlink=National Health Service|last2=|first2=|authorlink2=|date=Sep 7, 2020|website=|archive-url=|archive-date=|url-status=|access-date=}}</ref><ref name="Yellin2020" />

{{Quote box|“A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back|source=Dr. Nisreen Alwan, BMJ, Sep 2020}}

== COVID-19 testing ==
While some people with long COVID did have a positive test result for COVID-19, others were denied tests due to the limited availability of tests at the time, or they tested negative but were found to have clear evidence of COVID-19 from blood count tests or chest X-rays.<ref name="NIHR15Oct2020">{{Cite web|url=https://evidence.nihr.ac.uk/themedreview/living-with-covid19|title=Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid).|last=NIHR|first=|authorlink=|last2=|first2=|authorlink2=|date=October 2020|website=evidence.nihr.ac.uk|language=en-GB|archive-url=|archive-date=|url-status=|access-date=2020-10-15}}</ref><ref name="Kingstone2020" /> Some people with Long COVID have described never having a cough or fever at the start of their illness, but developed these symptoms later. Long COVID diagnosis does not depend on a previous positive test.<ref name="NIHR15Oct2020" /><ref name="Kingstone2020" />

==Evidence of symptoms ==

There is no blood test or diagnostic biomarker to identify patients with long COVID. A study in the UK found that just over 10% of long COVID patients had abnormal findings on the standard tests and did not find an association between standard test results and degree of organ damage or long COVID severity.<ref name="Dennis2020" /> The same study used MRI scans combined with patient questionnaires to assess organ damage, finding that multi-organ impairment was common in people with long COVID, despite the fact that 80% had not been hospitalized for [[COVID-19]], the average patient age was forty-four years old, and rates of pre-existing conditions were also low.<ref name="Dennis2020" />

==Research ==
Surveys of data collected and published by long haulers using social media were the first evidence of what symptoms and health problems were caused by long COVID.<ref name="bodypoliticMay2020" /> Later academic studies confirmed many of the initial long hauler survey findings, although many only involved patients discharged from hospital,<ref name="Puntmann2020" /> patients who had been able to access early testing and tested positive, or patients who had sought medical care in a particular location.<ref name="Arnold2020b" /> People with mild COVID-19 symptoms, leaving people denied testing and those who may have had false negative test results and people who tested positive but were asymptomatic underrepresented in long COVID research.<ref name="bodypoliticMay2020" />

==Treatment==

===Pacing===
Pacing is a method of activity management which aims to adapt everday activities in order to avoid relapses or increased symptoms.
{{See also|Pacing}}

===Exercise therapy ===
ME/CFS patient groups have raised concerns about the use of [[graded exercise therapy]] (GET) in long COVID patients and a similar warning has been issued by [[NICE]] in the [[United Kingdom|UK]].<ref name="GETcovidForwardME" /> Graded exercise therapy, which is sometimes incorrectly referred to as "activity management" involves patients initially reducing their activity levels to a level that prevents regular crashes, and then typically increasing activity by 10% each week regardless of any increased symptoms or worsening illness. In graded exercise patients are told to ignore deterioration or increased symptoms and "push through" them.

====Theory and evidence ====
In graded exercise therapy patients are told that their symptoms are caused only by [[deconditioning|inactivity]] and other "bad habits" rather than an underlying illness. These assumptions have very weak evidence, and significant evidence exists of underlying illness in ME/CFS; there is a lack of research about exercise therapy for long COVID illness<ref name="Navabi2020" /> but some symptoms are inconsistent with this "deconditioning" assumption and some research has found physical abnormalities in some patients weeks or month after infection. Surveys of ME/CFS patients have consistently shown that large numbers of patients deteriorate as a result of graded exercise therapy, and a significant number become severely ill and never return to the level of functioning they had before the treatment.

==ME/CFS==
[[Postviral fatigue syndrome]] is one of the previous names used for [[Myalgic Encephalomyelitis]] (ME), sometimes known as [[Chronic fatigue syndrome|Chronic Fatigue Syndrome]] (CFS), and it commonly begins immediately after events such as a virus, bacterial or other infection.<ref name="ICC2011primer">{{citation
| last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers
| last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande
| last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick
| last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell
| last7 = Staines | first7 = D | authorlink7 = Donald Staines
| last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles
| last9 = Speight | first9 = N | authorlink9 = Nigel Speight
| last10 = Vallings | first10= R | authorlink10= Rosamund Vallings
| last11 = Bateman | first11= L | authorlink11= Lucinda Bateman
| last12 = Bell | first12= DS | authorlink12= David Bell
| last13 = Carlo-Stella | first13= N | authorlink13= Nicoletta Carlo-Stella
| last14 = Chia | first14= J | authorlink14= John Chia
| last15 = Darragh | first15= A | authorlink15= Austin Darragh
| last16 = Gerken | first16= A | authorlink16= Anne Gerken
| last17 = Jo | first17= D | authorlink17= Daehyun Jo
| last18 = Lewis | first18= DP | authorlink18= Donald Lewis
| last19 = Light | first19= AR | authorlink19= Alan Light
| last20 = Light | first20= KC | authorlink20= Kathleen Light
| last21 = Marshall-Gradisnik | first21= S | authorlink21= Sonya Marshall-Gradisnik
| last22 = McLaren-Howard | first22= J | authorlink22= John McLaren-Howard| last23 = Mena | first23= I | authorlink23= Ismael Mena
| last24 = Miwa | first24= K | authorlink24= Kunihisa Miwa
| last25 = Murovska | first25= M | authorlink25= Modra Murovska
| last26 = Stevens | first26= SR | authorlink26= Staci Stevens
| title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners
| date = 2012| isbn = 978-0-9739335-3-6| url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf
}}</ref> ME has been a sequela of over [[Epidemic myalgic encephalomyelitis|one hundred outbreaks]], in addition to sporadic infections. ME/CFS is not normally diagnosed until symptoms have persisted for six months or more, and tests must be run to exclude other possible causes of the symptoms.<ref name="SEID2015">{{Citation|last=Institute of Medicine|author-link=Institute of Medicine|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|location=Washington, DC|publisher=The National Academies Press|date=2015|url=https://www.ncbi.nlm.nih.gov/books/NBK284902/}}</ref> Some contagious diseases including [[Epstein-Barr virus]], certain [[enterovirus]]es,<ref name="ICC2011primer" /> and the [[Severe acute respiratory syndrome|SARS]] coronavirus,<ref name="Moldofsky2011" /> have caused outbreaks of ME/CFS. It is not yet known how likely it is for ME/CFS to begin immediately after COVID-19 illness, although around 10% people with certain viruses are known to develop ME/CFS, and according to [[the BMJ]] around 10% of people with COVID-19 have developed long COVID. A significant number of those with long COVID have been found to develop ME/CFS, but it is not known how common this is.<ref name="BMJ11Aug2020" /><ref name="NIHR15Oct2020" />

==Patient surveys ==
'''Not peer reviewed'''
* May 2020, [https://patientresearchcovid19.com/research/report-1/ What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team]<ref name="bodypoliticMay2020">{{Cite web|url=https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic|title=What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team|date=May 11, 2020|vauthors=Assaf G, Davis H, McCorkell L, Wei H, O'Neil B, Akrami A, Low R, Mercier J, A A, L T, C A, S M, N L, H N, D JD, S}}</ref> - by [[Body Politic|Body Politic and Patient Led Research Collaborative]]
::Data collected: Apr 21 - May 2 2020. Respondents: 640

* Jul 2020, [https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf COVID-19 “Long Hauler” Symptoms Survey Report]<ref name="Lambert25Jul2020">{{Cite web|url=https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf|title=COVID-19 “Long Hauler” Symptoms Survey Report|last=Lambert|first=Natalie J|author-link=Natalie Lambert|last2=Survivor Corps|author-link2=Survivor Corps|publisher=Indiana University School of Medicine|date=Jul 2020}}</ref> - with Survivor Corps
::Data collected: Jul 25, 2020. Respondents: 1,567+
::
:* Dec 2020, [https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2 Charactering Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact] - by [https://patientresearchcovid19.com/ Body Politic and Patient Led Research Collaborative]
:** Respondents: 3,762+

==Notable studies==
*Jul 24, 2020, Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)<ref name="Puntmann2020">{{Cite journal|last=Puntmann|first=Valentina O.|last2=Carerj|first2=M. Ludovica|last3=Wieters|first3=Imke|last4=Fahim|first4=Masia|last5=Arendt|first5=Christophe|last6=Hoffmann|first6=Jedrzej|last7=Shchendrygina|first7=Anastasia|last8=Escher|first8=Felicitas|last9=Vasa-Nicotera|first9=Mariuca|date=2020-07-27|title=Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)|url=https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916|journal=JAMA Cardiology|language=en|doi=10.1001/jamacardio.2020.3557|issn=2380-6583}}</ref> - [https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 (Full text)]
*Aug 11, 2020, Management of post-acute covid-19 in primary care<ref name="BMJ11Aug2020">{{cite journal|title=Management of post-acute covid-19 in primary care|last=Greenhalgh|first=Trisha|author-link =Trisha Greenhalgh|first2=Matthew|last2=Knight|author-link2=Matthew Knight|author-link3=Christine A'Court|first3=Christine|last3=A'Court|first4=Maria|last4=Buxton|first5= Laiba|last5=Husain|journal=The BMJ|date=Aug 11, 2020|volume=370|doi=10.1136/bmj.m3026|pages=m3026|url =https://doi.org/10.1136/bmj.m3026}}</ref> - [https://doi.org/10.1136/bmj.m3026 (Full text)]
*Aug 20, 2020, New-Onset Diabetes in Covid-19<ref name="Rubino2020" /> - [https://www.nejm.org/doi/full/10.1056/NEJMc2018688 (Full text)]
*Oct 1, 2020, Long-term consequences of COVID-19: research needs<ref name="Yellin2020">{{Cite journal|last=Yelin|first=Dana|last2=Wirtheim|first2=Eytan|last3=Vetter|first3=Pauline|last4=Kalil|first4=Andre C.|last5=Bruchfeld|first5=Judith|last6=Runold|first6=Michael|last7=Guaraldi|first7=Giovanni|last8=Mussini|first8=Cristina|last9=Gudiol|first9=Carlota|date=2020-10-01|title=Long-term consequences of COVID-19: research needs|url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/abstract|journal=The Lancet Infectious Diseases|language=English|volume=20|issue=10|pages=1115–1117|doi=10.1016/S1473-3099(20)30701-5|issn=1473-3099|pmid=32888409}}</ref> - [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext (Full text)]
*Oct 14, 2020, Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID<ref name="Kingstone2020">{{Cite journal|last=Kingstone|first=Tom|author-link=|last2=Taylor|first2=Anna K.|author-link2=|last3=O'Donnell|first3=Catherine A.|author-link3=|last4=Atherton|first4=Helen|author-link4=|last5=Blane|first5=David N.|author-link5=|last6=Chew-Graham|first6=Carolyn A.|author-link6=Carolyn Chew-Graham|date=2020-10-14|title=Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID|url=https://bjgpopen.org/content/early/2020/10/12/bjgpopen20X101143|journal=BJGP Open|language=en|volume=|issue=|pages=|doi=10.3399/bjgpopen20X101143|issn=2398-3795|pmc=|pmid=33051223|access-date=|quote=|via=}}</ref> - [https://bjgpopen.org/content/bjgpoa/early/2020/10/12/bjgpopen20X101143.full.pdf (Full text)]
*Oct 16, 2020, Multi-organ impairment in low-risk individuals with long COVID<ref name="Dennis2020">{{Cite journal|last=Dennis|first=Andrea|author-link=|last2=Wamil|first2=Malgorzata|author-link2=|last3=Kapur|first3=Sandeep|author-link3=|last4=Alberts|first4=Johann|author-link4=|last5=Badley|first5=Andrew D.|author-link5=|last6=Decker|first6=Gustav Anton|author-link6=|last7=Rizza|first7=Stacey A.|last8=Banerjee|first8=Rajarshi|last9=Banerjee|first9=Amitava|author-link9=Amitava Banerjee|date=2020-10-16|title=Multi-organ impairment in low-risk individuals with long COVID|url=https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.14.20212555|doi=10.1101/2020.10.14.20212555|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.1101/2020.10.14.20212555 (Full text)]
*Oct 21, 2020, Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App<ref name="Sudre2020a">{{Cite journal|last=Sudre|first=Carole H.|author-link=|last2=Murray|first2=Benjamin|author-link2=|last3=Varsavsky|first3=Thomas|author-link3=|last4=Graham|first4=Mark S.|author-link4=|last5=Penfold|first5=Rose S.|author-link5=|last6=Bowyer|first6=Ruth C.|author-link6=|last7=Pujol|first7=Joan Capdevila|last8=Klaser|first8=Kerstin|last9=Antonelli|first9=Michela|date=2020-10-19|others=|title=Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App|url=https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.19.20214494|doi=10.1101/2020.10.19.20214494|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1.full-text (Full text)]
*Dec 2020 (pre-print) / Jul 15, 2021, Characterizing long COVID in an international cohort: 7 months of symptoms and their impact<ref name="Davis2021a">{{Cite journal|last=Davis|first=Hannah E.|last2=Assaf|first2=Gina S.|last3=McCorkell|first3=Lisa|last4=Wei|first4=Hannah|last5=Low|first5=Ryan J.|last6=Re'em|first6=Yochai|last7=Redfield|first7=Signe|last8=Austin|first8=Jared P.|last9=Akrami|first9=Athena|date=2021-07-15|title=Characterizing long COVID in an international cohort: 7 months of symptoms and their impact|url=https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/abstract|journal=EClinicalMedicine|language=English|volume=0|issue=0|doi=10.1016/j.eclinm.2021.101019|issn=2589-5370}}</ref> - [https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/abstract (Abstract)]
*Dec 20, 2020, Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort<ref name="Arnold2020b">{{Cite journal|last=Arnold|first=David T.|author-link=David Arnold|last2=Hamilton|first2=Fergus W.|last3=Milne|first3=Alice|last4=Morley|first4=Anna J.|last5=Viner|first5=Jason|last6=Attwood|first6=Marie|last7=Noel|first7=Alan|last8=Gunning|first8=Samuel|last9=Hatrick|first9=Jessica|date=2021-04-01|title=Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort|url=https://thorax.bmj.com/content/76/4/399|journal=Thorax|language=en|volume=76|issue=4|pages=399–401|doi=10.1136/thoraxjnl-2020-216086|issn=0040-6376|pmid=33273026}}</ref> - [https://thorax.bmj.com/content/76/4/399 (Full text)] - from the DISCOVER project
*Jan 18, 2021, Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome?<ref name="Komaroff2021a">{{Cite journal|last=Komaroff|first=Anthony L.|author-link=Anthony Komaroff|last2=Bateman|first2=Lucinda|author-link2=Lucinda Bateman|date=2021|title=Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?|url=https://www.frontiersin.org/articles/10.3389/fmed.2020.606824/full?s=03|journal=Frontiers in Medicine|language=English|volume=|issue=|pages=|doi=10.3389/fmed.2020.606824|issn=2296-858X|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.frontiersin.org/articles/10.3389/fmed.2020.606824/full?s=03 (Full text)]
*Mar 27, 2021, COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection<ref name="Lambert2021a">{{Cite journal|last=Lambert|first=Natalie|author-link=Natalie Lambert|last2=Corps|first2=Survivor|author-link2=Survivor Corps|last3=El-Azab|first3=Sarah A.|author-link3=|last4=Ramrakhiani|first4=Nathan S.|author-link4=|last5=Barisano|first5=Anthony|author-link5=|last6=Yu|first6=Lu|author-link6=|last7=Taylor|first7=Kaitlyn|last8=Esperanca|first8=Alvaro|last9=Downs|first9=Charles A.|date=2021-03-27|title=COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection|url=https://www.medrxiv.org/content/10.1101/2021.03.22.21254026v2|journal=medRxiv|language=en|volume=|issue=|pages=2021.03.22.21254026|doi=10.1101/2021.03.22.21254026|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.1101/2021.03.22.21254026 (Full text)]
*May 11, 2021, Mayo Clinic Proceedings: Post COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at the Mayo Clinic and Characteristics of the Initial Patient Cohort<ref name="mayo2021a">{{Cite journal|last=Vanichkachorn|first=Greg|last2=Newcomb|first2=Richard|last3=Cowl|first3=Clayton T.|last4=Murad|first4=M. Hassan|last5=Breeher|first5=Laura|last6=Miller|first6=Sara|last7=Trenary|first7=Michael|last8=Neveau|first8=Daniel|last9=Higgins|first9=Steven|date=2021-07-01|title=Post–COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at Mayo Clinic and Characteristics of the Initial Patient Cohort|url=https://www.mayoclinicproceedings.org/article/S0025-6196(21)00356-6/abstract|journal=Mayo Clinic Proceedings|language=English|volume=96|issue=7|pages=1782–1791|doi=10.1016/j.mayocp.2021.04.024|issn=0025-6196|pmid=34218857}}</ref> - [https://www.mayoclinicproceedings.org/article/S0025-6196(21)00356-6/abstract (Abstract)]
*Jun 7, 2021, Insights from ME/CFS May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome<ref name="Komaroff2021b">{{Cite journal|last=Komaroff|first=Anthony L.|author-link=Anthony Komaroff|last2=Lipkin|first2=W. Ian|author-link2=Ian Lipkin|date=2021-06-07|title=Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome|url=https://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(21)00134-9|journal=Trends in Molecular Medicine|language=English|volume=|issue=|pages=|doi=10.1016/j.molmed.2021.06.002|issn=1471-4914|pmc=|pmid=34175230|access-date=|quote=|via=}}</ref> - [https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(21)00134-9 (Full text)]
*Jun 23, 2021, Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms<ref name="Proal2021">https://doi.org/10.3389/fmicb.2021.698169</ref> - [https://doi.org/10.1101/2020.12.24.20248802 (Full text)]

==Articles and editorials ==
*Jun 15, 2021, White Paper: A Detailed Study of Patients with Long-Haul COVID<ref name="Fairthealth2021">{{Cite web|url=https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf|publisher=FAIR Health|date=Jun 18, 2020|title=A Detailed Study of Patients with Long-Haul COVID: An Analysis of Private Healthcare Claims. A FAIR Health White Paper}}</ref> [https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf (Full text)]
*Jun 24, 2021, Covid-19: Third of people infected have long term symptoms<ref name="ODowd2021">{{Cite journal|last=O’Dowd|first=Adrian|date=2021-06-24|title=Covid-19: Third of people infected have long term symptoms|url=https://www.bmj.com/content/373/bmj.n1626|journal=BMJ|language=en|volume=373|pages=n1626|doi=10.1136/bmj.n1626|issn=1756-1833|pmid=34168002}}</ref> [https://www.bmj.com/content/373/bmj.n1626 (Editorial)]

==Presentations, interviews and videos==
*Aug 2020, [https://solvecfs.org/wp-content/uploads/2020/08/Post-COVID%20ME-to%20Solve.pdf Will Covid-19 lead to ME/CFS in some people?] - presentation - Dr [[Anthony Komaroff]]
*Jul 2020, [https://www.youtube.com/watch?v=IIeOoS_A4c8 Message in a Bottle] video - [[LongCovidSOS]]
*Jun 2020, [https://www.biomax.com/lib/press-releases/Initial-Result-Announcment_English.pdf Health of Corona Patients at Home in Alarmingly Poor Health Even After Several Months - Dutch Lung Foundation] - Press release (English translation) - [https://www.ad.nl/binnenland/longfonds-gezondheid-thuiszittende-coronapatienten-schrikbarend-slecht~a45346fe/ Dutch]

==Letters and blogs==
*May 2020, [http://somatosphere.net/2020/mild-covid.html/ Very, very mild: Covid-19 symptoms and illness classification] - [[Felicity Callard]]
*Jul 2020, [https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf Letter re Covid-19 Management and Exercise Caution]<ref name="GETcovidForwardME">{{Cite web|url=https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf|date=2020-08-27|last=Forward-ME|author-link=Forward-ME|title =Letter re Covid-19 Management and Exercise Caution}}</ref> - [[Forward-ME]]
*Sep 2020, [https://mecfsresearchreview.me/2020/09/17/understanding-long-covid-a-shortcut-to-solving-me-cfs/?#symptoms Understanding Long Covid, A Shortcut to Solving ME/CFS?] - [[Simon McGrath]]
*Sep 2020, [https://wellcomeopenresearch.org/articles/5-224 Why the Patient-Made Term 'Long Covid' is needed] - Open Letter
*Oct 2020, [https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/ Why we need to keep using the patient made term “Long Covid”] - [[The BMJ]]
*January 2021, [https://directorsblog.nih.gov/tag/post-acute-sequelae-of-covid-19/ Trying to Make Sense of Long COVID Syndrome] - Dr. Francis Collins, CDC director

==National and international health bodies==
*[https://doi.org/10.1136/bmj.m2912 NICE cautions against using graded exercise therapy for patients recovering from COVID-19]<ref name="NICEcautionBMJ">{{Cite journal|last=Torjesen|first=Ingrid|date=2020-07-21|title=NICE cautions against using graded exercise therapy for patients recovering from covid-19|url=https://www.bmj.com/content/370/bmj.m2912|journal=The BMJ|language=en|volume=370|doi=10.1136/bmj.m2912|issn=1756-1833|pmid=32694164}}</ref>

==News articles ==
* Oct 2020, [https://www.theguardian.com/world/2020/oct/21/women-aged-50-60-at-greatest-risk-of-long-covid-experts-suggest Women aged 50-60 at greatest risk of ‘long Covid’, experts suggest] - The Guardian

* Oct 2020, [https://www.wsj.com/articles/these-doctors-have-long-term-covid-now-theyre-pushing-for-better-care-11603144474 These Doctors Have Long-Term Covid. Now They’re Pushing for Better Care.] - Wall Street Journal
* Oct 2020, [https://time.com/5897992/long-haul-coronavirus-me-cfs/ Have We Been Thinking About Long-Haul Coronavirus All Wrong?] - Time
* Oct 2020, [https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891 Living with COVID: NIHR publishes dynamic-themed review into 'ongoing COVID'] - National Institute of Health Research
* Oct 2020, [https://www.theguardian.com/world/2020/oct/04/long-covid-the-evidence-of-lingering-heart-damage Long Covid: the evidence of lingering heart damage] - The Observer
* Sep 2020, [https://www.bbc.co.uk/news/uk-england-leicestershire-54106073 Coronavirus patient unable to work six months on] - BBC News
* Aug 2020, [https://www.huffingtonpost.co.uk/entry/long-term-symptoms-of-covid-19-identified-in-study-of-hospital-patients_uk_5f2bc0f6c5b64d7a55eefcfa The Most Common Long-Term Symptoms Of Covid-19] - HuffPost UK
* Jul 2020, [https://www.sciencemag.org/news/2020/07/brain-fog-heart-damage-covid-19-s-lingering-problems-alarm-scientists From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists] - Science Mag

==See also==
*[[List of famous people with long COVID]]
*[[List of open letters about long COVID]]
*[[Post-COVID-19 illness]]
*[[COVID-19]] coronavirus disease 19
*[[Myalgic encephalomyelitis|Myalgic encephalomyelitis and chronic fatigue syndrome]]
*[[Postviral fatigue syndrome]]
*[[Post-Ebola syndrome]]
*[[Encephalitis lethargica]]
*[[Paul Garner]]
*[[Nisreen Alwan]]

==Learn more==
*[https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects COVID-19 Long Term Health Effects]
*[https://www.bmj.com/sites/default/files/infographics/1353078336/static-infographic/background.png Infographic: "Long covid" in primary care] - BMJ journal
* List of long COVID studies (draft) - [[MEAction|#MEAction]]

==References==
{{reflist}}

[[Category:Potential comorbidities]]
[[Category:Diagnoses]]
[[Category:Long COVID]]

Clivo-axial angle

2020-12-30T01:47:10Z

JenB:/* Ehlers-Danlos Syndrome */

The '''clivo-axial angle''' (CXA) is a measure of the angle between the clivus, a bony part of the base of the skull, and the spine.<ref name=":0">[https://csfinfo.org/files/1613/9665/4797/Final_Booklet_complete.pdf Consensus statement. 2nd International CSF Dynamics Symposium, 2013.] </ref> It is used to aid in the diagnosis of [[craniocervical instability]]. It is sensitive to horizontal instability and characterizes the relationship between the skull, the brainstem, and the odontoid process, including abnormalities due for example, to a compromised [[transverse ligament]].

== Definitions ==
Also called the clivus canal angle, the clivus vertebral angle, the clivus spinal angle or the clivus cervical angle, terms and measurement methodology can vary from study to study and from neurosurgeon to neurosurgeon.<ref name=":4">{{Cite journal|last=Henderson|first=Fraser C.|last2=Henderson|first2=Fraser C.|last3=Wilson|first3=William A.|last4=Mark|first4=Alexander S.|last5=Koby|first5=Myles|date=2018-01-01|title=Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review|url=https://doi.org/10.1007/s10143-017-0830-3|journal=Neurosurgical Review|language=en|volume=41|issue=1|pages=149–163|doi=10.1007/s10143-017-0830-3|issn=1437-2320|pmc=PMC5748419|pmid=28258417}}</ref> In an effort to standardize terminology and measurement, a 2014 consensus statement defined the CXA as "the angle between the clivus line and the posterior axial line."<ref name=":4" /><ref name=":5">Batzdorf U, Henderson F, Rigamonti D (2016) Eds. ''Co-morbitidies that complicate the treatment and outcomes of chiari malformation.'' First edition ed. Chiari Syringomyelia Foundation Inc., Lulu</ref><blockquote>The clivus line is drawn along the lower third of the clivus, from the spheno-occipital synchondrosis to the basion; in the case of basilar invagination, it is drawn from the spheno-occipital synchondrosis to the top of the odontoid process. The posterior axial line is differentiated to reflect either the bone contour of the axis on CT, the so-called ''bone CXA'', or the ligamentous margin of the odontoid—the ''soft tissue CXA''. The soft tissue CXA, necessarily including thickening of the posterior ligament due to pannus, may be more pertinent in identifying possible ventral brainstem compression, and is therefore more representative of the pathology.<ref name=":4" /><ref name=":5" /></blockquote>

== Epidemiology ==
The average CXA in healthy or nonsymptomatic population is estimated to be approximately 150 degrees. Several studies have shown that a CXA lower than 135 degrees, a frequently used cutoff, is uncommon in the healthy population<ref name=":1">{{Cite journal|last=Botelho|first=Ricardo Vieira|last2=Ferreira|first2=Edson Dener Zandonadi|date=Oct 2013|title=Angular craniometry in craniocervical junction malformation|url=https://www.ncbi.nlm.nih.gov/pubmed/23640096|journal=Neurosurgical Review|volume=36|issue=4|pages=603–610; discussion 610|doi=10.1007/s10143-013-0471-0|issn=1437-2320|pmc=3910287|pmid=23640096}}</ref><ref name=":2">{{Cite journal|last=Batista|first=Ulysses C.|last2=Joaquim|first2=Andrei F.|last3=Fernandes|first3=Yvens B.|last4=Mathias|first4=Roger N.|last5=Ghizoni|first5=Enrico|last6=Tedeschi|first6=Helder|date=Apr 2015|title=Computed tomography evaluation of the normal craniocervical junction craniometry in 100 asymptomatic patients|url=https://www.ncbi.nlm.nih.gov/pubmed/25828499|journal=Neurosurgical Focus|volume=38|issue=4|pages=E5|doi=10.3171/2015.1.FOCUS14642|issn=1092-0684|pmid=25828499}}</ref><ref name=":3">{{Cite journal|last=Bundschuh|first=C|last2=Modic|first2=Mt|last3=Kearney|first3=F|last4=Morris|first4=R|last5=Deal|first5=C|date=1988-07-01|title=Rheumatoid arthritis of the cervical spine: surface-coil MR imaging|url=https://www.ajronline.org/doi/abs/10.2214/ajr.151.1.181|journal=American Journal of Roentgenology|volume=151|issue=1|pages=181–187|doi=10.2214/ajr.151.1.181|issn=0361-803X}}</ref> (see table below) and is associated with pathological conditions such as brainstem compression in patients with [[rheumatoid arthritis]].<ref name=":3" /> A consensus statement formed at the second International CSF Dynamics Symposium of the Chiari and Syringomyelia Foundation in 2013, proposed that a CXA lower than 135 degrees could be seen as “potentially pathological.”<ref name=":0" />
{| class="wikitable"
!Study
!Term
!Definition
!Number of healthy persons
!Average CXA
!standard deviation
!Range
|-
|Bothelo & Ferreira (2013)<ref name=":1" />
|Clivo-canal angle (CCA)
|The angle between the line extending from the top of the dorsum sellae to the basion and the line between the inferodorsal portions of C2 to the most superodorsal part of the dens.<ref name=":1" />
|33
|148°
|± 9.8°
|129°-175°
|-
|Batista et al. (2015)<ref name=":2" />
|Clivus-canal angle (CCA)
|Measured as the angle at the intersection of a line extending from the inferior one-third of the clivus and a line extending from the inferodorsal portion of the C-2 vertebral body to the superodorsal part of the dens<ref name=":2" />
|100
|153.6°
|± 7.6°
|132.3°–173.9°
|-
|Bundschuh et al. (1987)<ref name=":3" />
|Cervicomedullary angle
|Angle subtended by lines drawn parallel to the ventral surfaces of the medulla and upper cervical cord<ref name=":3" />
|50
|155.2°
|± 8,7°
|135°-175°
|-
|Asal and Hasan (2018)<ref name=":7" />
|Clivo-axial angle (CAA)
|The angle between the line extending from dorsum sella to basion and the line drawn along the boundary superoposterior and inferoposterior corners of the C2 vertebrae.<ref name=":7" />
|65
|153.66°
|±6.35°
|139.5-169.5
|-
|Nagashima and Kubota (1983)<ref name=":6">{{Cite journal|last=Nagashima|first=C.|last2=Kubota|first2=S.|date=1983|title=Craniocervical abnormalities. Modern diagnosis and a comprehensive surgical approach|url=https://www.ncbi.nlm.nih.gov/pubmed/6674836|journal=Neurosurgical Review|volume=6|issue=4|pages=187–197|issn=0344-5607|pmid=6674836}}</ref>
|Clivo-axial angle (C-A angle)
|The clivus line (line drawn along posterior surface of clivus) and the axis line (line drawn along posterior surface of axis) form the angle.<ref name=":6" />
|41
|158.2°
|± 9.8°
|
|}

=== Gender ===
Women have increased range of motion (change in CXA from flexion to extension) than men.<ref name=":6" />

===ME/CFS ===
A Swedish study of 234 ME/CFS patients meeting the [[Canadian Consensus Criteria]] found an average CXA of f 148 ±10 degrees<ref>{{Cite journal|last=Bragée|first=Björn|last2=Michos|first2=Anastasios|last3=Drum|first3=Brandon|last4=Fahlgren|first4=Mikael|last5=Szulkin|first5=Robert|last6=Bertilson|first6=Bo C.|date=2020-08-28|title=Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/article/10.3389/fneur.2020.00828/full|journal=Frontiers in Neurology|volume=11|pages=828|doi=10.3389/fneur.2020.00828|issn=1664-2295}}</ref>, measured as:<blockquote>A straight line was drawn along the caudal edge of the clivus bone, and a second was drawn by extending a straight line along the posterior axial line from the base of the axis to the dens</blockquote>

=== Ehlers-Danlos Syndrome ===
A study of the CXA in patients with [[Ehlers-Danlos syndrome]] and a control group of patients with cervical spondolysis found that EDS patients had an average CXA of 139.7±10.4 degrees as compared to the control group 148.9±8.4. They also had a greater change in CXA between flexion and extension: 74.6±24.4 in the EDS group vs 39.4±11.3 in controls.<ref>{{Cite journal|last=Casey|first=A. T.|last2=Smith|first2=F.|last3=Davagnanam|first3=I.|last4=Khan|first4=F.|last5=Prezerakos|first5=G. K.|date=2019-03-01|title=FM1-7 Cranio-cervical instability in ehlers-danlos syndrome employing upright, dynamic MR imaging; a comparative study|url=https://jnnp.bmj.com/content/90/3/e22.2|journal=Journal of Neurology, Neurosurgery & Psychiatry|language=en|volume=90|issue=3|pages=e22–e22|doi=10.1136/jnnp-2019-ABN.69|issn=0022-3050}}</ref>

=== Migraine ===
The clivo-axial angle of 65 patients with [[migraine]] and 65 controls were compared. The mean CXA in the migraine group was 142.65 ± 8.73°, 153.66 ± 6.35° in controls.<ref name=":7">{{Cite journal|last=Şahan|first=Mehmet Hamdi|last2=Asal|first2=Neşe|date=2018-12-01|title=Is there a relationship between migraine disease and the skull base angles?|url=https://dergipark.org.tr/ortadogutipdergisi/issue/40670/411138|journal=Ortadoğu Tıp Dergisi|language=en|volume=10|issue=4|pages=456–470|doi=10.21601/ortadogutipdergisi.411138|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref>

=== Basilar invagination ===
Bothelo & Ferreira (2013) documented 25 patients with [[basilar invagination]] and found a mean CXA of 120° (range 79°–145°).<ref name=":1" />

== References ==
{{reflist}}
[[Category:Neurology]]

Neuroimaging

2020-12-24T17:40:58Z

JenB:

'''Neuroimaging''' or is the use of various techniques to either directly or indirectly image the structure, function, or pharmacology of the [[nervous system]].

== Imaging techniques ==
A wide range of techniques can be used to measure the structure and function of the brain. Some techniques are commonly used in clinical practice, while others are either experimental or predominantly used in research settings.

=== Electroencephalography (EEG) ===
{{Main article|page_name=Electroencephalography}}Insert short description here

=== Magnetic Resonance Imaging (MRI) ===
{{Main article|page_name=Magnetic resonance imaging}}

Insert short description here

=== Functional magnetic resonance imaging (fMRI) ===
{{Main|page_name=Functional magnetic resonance imaging}}

Insert short description here

=== Computed tomography (CT) ===
{{Main article|page_name=Computed tomography scan}}

Insert short description here

=== Position Emission Tomography (PET) ===
{{Main article|page_name=Positron emission tomography}}

Insert short description here

=== Near InfraRed Spectroscopy (NIRS) ===
{{Main|page_name=Near InfraRed Spectroscopy}}

Insert short description here

=== Magnetoencephalography (MEG) ===
{{Main|page_name=Magnetoencephalography}}

Insert short description here

== List of common clinical neuroimaging ==
* [[X-ray]]
* [[Fluroscopy]]
* [[Computed tomography scan]] (CT scan)
* [[Positron emission tomography]] ([[PET scan]]) or PET-CT
* [[Magnetic Resonance Imaging]] ([[MRI]]) of the brain or spine (cervical, thoracic, lumbar, sacrum)
* [[Magnetic Resonance Angiography]] ([[MRA]])
* [[Magnetic Resonance Venography]] ([[MRV]])
* [[Upright MRI]]
* [[CT myelogram]]

=== Dynamic imaging ===
Dynamic components can be added to many common imaging techniques to see how structure and function change in different positions. For example, a cervical MRI can be take in a neutral position, and compared to images taken of the neck in flexion and extension. This can aid in the diagnosis of [[Chiari malformation]], [[Cerebellar tonsillar herniation]], [[Craniocervical instability]], and positional cord compression due to [[Cervical spinal stenosis]]. A cervical CT scan can be taken of the neck in neutral as compared to left and right positions to aid in the diagnosis of [[Atlantoaxial instability]].

Other types of imaging seek to observe the dynamic flow of fluid in the nervous system. For example, a [[cine MRI]] is used to observe cerebral spinal fluid flow, which can be obstructed in some conditions, such as [[Chiari malformation|Chiari]].

=== Interventional radiology ===
* [[Invasive angiogram]]
* [[Invasive venogram]]

== List of research neuroimaging ==
*

== Related ==
* [[Brain]]
* [[Spine]]

== See also ==
* [https://radiopaedia.org/?lang=us Radiopaedia.org]

== References ==

Neuroimaging

2020-12-24T17:36:06Z

JenB:

'''Neuroimaging''' or is the use of various techniques to either directly or indirectly image the structure, function, or pharmacology of the [[nervous system]].

== Imaging techniques ==
A wide range of techniques can be used to measure the structure and function of the brain. Some techniques are commonly used in clinical practice, while others are either experimental or predominantly used in research settings.

=== Electroencephalography (EEG) ===
Magnetic Resonance Imaging (MRI)

Functional magnetic resonance imaging (fMRI)

Computed tomography (CT)

Position Emission Tomography (PET)

Near InfraRed Spectroscopy (NIRS)

Magnetoencephalography (MEG)

== List of common clinical neuroimaging ==
* X-ray
* Fluroscopy
* [[Computed tomography scan]] (CT scan)
* Positron emission tomography (PET scan) or PET-CT
* Magnetic Resonance Imaging (MRI) of the brain or spine (cervical, thoracic, lumbar, sacrum)
* Magnetic Resonance Angiography (MRA)
* Magnetic Resonance Venography (MRV)
* [[Upright MRI]]
* CT myelogram

=== Dynamic imaging ===
Dynamic components can be added to many common imaging techniques to see how structure and function change in different positions. For example, a cervical MRI can be take in a neutral position, and compared to images taken of the neck in flexion and extension. This can aid in the diagnosis of [[Chiari malformation]], [[Cerebellar tonsillar herniation]], [[Craniocervical instability]], and positional cord compression due to [[Cervical spinal stenosis]]. A cervical CT scan can be taken of the neck in neutral as compared to left and right positions to aid in the diagnosis of [[Atlantoaxial instability]].

Other types of imaging seek to observe the dynamic flow of fluid in the nervous system. For example, a [[cine MRI]] is used to observe cerebral spinal fluid flow, which can be obstructed in some conditions, such as [[Chiari malformation|Chiari]].

=== Interventional radiology ===
* Invasive angiogram
* Invasive venogram

== List of research neuroimaging ==
*

== Related ==
* [[Brain]]
* [[Spine]]

== See also ==
* [https://radiopaedia.org/?lang=us Radiopaedia.org]

== References ==

Computed tomography scan

2020-12-24T17:26:20Z

JenB:Create page

A computed tomography (CT) scan combines a series of X-ray images taken from different angles around your body and uses computer processing to create cross-sectional images (slices) of the bones, blood vessels and soft tissues inside your body. CT scan images provide more-detailed information than plain X-rays do.

Neuroimaging

2020-12-24T17:15:17Z

JenB:Created redirect

#redirect [[Brain imaging]]

List of clinical laboratory tests

2020-12-24T17:14:52Z

JenB:Added US ME/CFS Clinician Coalition

There are no established biomarkers for [[myalgic encephalomyelitis]] or many of its [[comorbidities]]. The following are clinically available lab tests used by some practitioners to aid in [[differential diagnosis]] or management of patients’ condition.

{| class="wikitable"
!Test name
!Type
!Description
!Rationale
!Relevant diagnoses
!Commercial availability
|-
|[[Matrix metalloproteinase]]-9
|Serum
|MMP-9 is a marker of inflammation, tissue remodeling, wound healing, and mobilization of tissue-bound growth factors and cytokines. Its expression correlates with abnormal collagen deposition accompanying pancreatic cancer, with lymph node metastasis in breast cancer and with regional vessel invasion by giant cell tumor or bone. MMP-9 contributes to the pathogenesis of numerous clinical disease states, including rheumatic arthritis, coronary artery disease, chronic obstructive pulmonary disease, multiple sclerosis, asthma, and cancer.
|
|
|[https://www.labcorp.com/tests/500124/mmp-9-matrix-metalloproteinase-9 Labcorp]
|-
|[[Hydroxyproline]]
|Urine
|Hydroxyproline is an amino acid present in appreciable quantities in collagen and excreted in the urine after collagen breakdown. Because urinary hydroxyproline is derived almost entirely from collagen, it reflects the rate of collagen catabolism.
|
|
|[https://www.labcorp.com/tests/700140/amino-acid-profile-quantitative-urine Labcorp], [http://questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Hydroxyproline_24Hour_Urine.pdf Quest]
|-
|[[Hydroxyproline]]
|Plasma
|
|
|
|[https://www.labcorp.com/tests/700068/amino-acid-profile-quantitative-plasma Labcorp], [https://testdirectory.questdiagnostics.com/test/test-detail/37558/hydroxyproline-plasma?cc=MASTER Quest]
|-
|[[Hydroxylysine]]
|Urine
|
|
|
|
|-
|[[Hydroxylysine]]
|Plasma
|
|
|
|
|}

== Related ==
* [[Neuroimaging]]

== See also ==
* [https://mecfscliniciancoalition.org/clinical-management/#diagnosisandmanagement US ME/CFS Clinician Coalition: Guidance on Diagnosis and Management]
* [https://tmsforacure.org/tests/ The Mast Cell Disease Society: Tests for Mast Cell Activation]

== References ==

List of clinical laboratory tests

2020-12-24T17:13:43Z

JenB:Added MCD link

There are no established biomarkers for [[myalgic encephalomyelitis]] or many of its [[comorbidities]]. The following are clinically available lab tests used by some practitioners to aid in [[differential diagnosis]] or management of patients’ condition.

{| class="wikitable"
!Test name
!Type
!Description
!Rationale
!Relevant diagnoses
!Commercial availability
|-
|[[Matrix metalloproteinase]]-9
|Serum
|MMP-9 is a marker of inflammation, tissue remodeling, wound healing, and mobilization of tissue-bound growth factors and cytokines. Its expression correlates with abnormal collagen deposition accompanying pancreatic cancer, with lymph node metastasis in breast cancer and with regional vessel invasion by giant cell tumor or bone. MMP-9 contributes to the pathogenesis of numerous clinical disease states, including rheumatic arthritis, coronary artery disease, chronic obstructive pulmonary disease, multiple sclerosis, asthma, and cancer.
|
|
|[https://www.labcorp.com/tests/500124/mmp-9-matrix-metalloproteinase-9 Labcorp]
|-
|[[Hydroxyproline]]
|Urine
|Hydroxyproline is an amino acid present in appreciable quantities in collagen and excreted in the urine after collagen breakdown. Because urinary hydroxyproline is derived almost entirely from collagen, it reflects the rate of collagen catabolism.
|
|
|[https://www.labcorp.com/tests/700140/amino-acid-profile-quantitative-urine Labcorp], [http://questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Hydroxyproline_24Hour_Urine.pdf Quest]
|-
|[[Hydroxyproline]]
|Plasma
|
|
|
|[https://www.labcorp.com/tests/700068/amino-acid-profile-quantitative-plasma Labcorp], [https://testdirectory.questdiagnostics.com/test/test-detail/37558/hydroxyproline-plasma?cc=MASTER Quest]
|-
|[[Hydroxylysine]]
|Urine
|
|
|
|
|-
|[[Hydroxylysine]]
|Plasma
|
|
|
|
|}

== Related ==
* [[Neuroimaging]]

== See also ==
* [https://tmsforacure.org/tests/ The Mast Cell Disease Society: Tests for Mast Cell Activation]

== References ==

List of clinical laboratory tests

2020-12-24T17:09:38Z

JenB:

List of clinical laboratory tests

2020-12-24T17:06:13Z

JenB:Added MMP-9, hydroxyproline, Hydroxylysine

There are no established biomarkers for [[myalgic encephalomyelitis]] or many of its [[comorbidities]]. The following are clinically available lab tests used by some practitioners to aid in differential diagnosis or management of patients’ condition.

{| class="wikitable"
!Test name
!Type
!Description
!Rationale
!Relevant diagnoses
!Commercial availability
|-
|[[Matrix metalloproteinase]]-9
|Serum
|MMP-9 is a marker of inflammation, tissue remodeling, wound healing, and mobilization of tissue-bound growth factors and cytokines. Its expression correlates with abnormal collagen deposition accompanying pancreatic cancer, with lymph node metastasis in breast cancer and with regional vessel invasion by giant cell tumor or bone. MMP-9 contributes to the pathogenesis of numerous clinical disease states, including rheumatic arthritis, coronary artery disease, chronic obstructive pulmonary disease, multiple sclerosis, asthma, and cancer.
|
|
|[https://www.labcorp.com/tests/500124/mmp-9-matrix-metalloproteinase-9 Labcorp]
|-
|[[Hydroxyproline]]
|Urine
|Hydroxyproline is an amino acid present in appreciable quantities in collagen and excreted in the urine after collagen breakdown. Because urinary hydroxyproline is derived almost entirely from collagen, it reflects the rate of collagen catabolism.
|
|
|[https://www.labcorp.com/tests/700140/amino-acid-profile-quantitative-urine Labcorp], [http://questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Hydroxyproline_24Hour_Urine.pdf Quest]
|-
|[[Hydroxyproline]]
|Plasma
|
|
|
|[https://www.labcorp.com/tests/700068/amino-acid-profile-quantitative-plasma Labcorp], [https://testdirectory.questdiagnostics.com/test/test-detail/37558/hydroxyproline-plasma?cc=MASTER Quest]
|-
|[[Hydroxylysine]]
|Urine
|
|
|
|
|-
|[[Hydroxylysine]]
|Plasma
|
|
|
|
|}

== See also ==
* [[Neuroimaging]]

== References ==

List of clinical laboratory tests

2020-12-24T16:54:06Z

JenB:Created