Comorbidities of Myalgic Encephalomyelitis

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A comorbidity is a diagnosis that commonly occurs independently of, and at the same time as another condition.[1] For example, Hashimoto's thyroiditis is a comorbidity of ME/CFS because they are independent conditions, but postural orthostatic tachychardia syndrome is a symptom used to aid the diagnosis of ME/CFS is not a comorbidity even though both are distinct disorders and both frequently occur together.[2][3] Symptoms of ME/CFS that are not a separate diagnosis are not counted as comorbidities.

Patients with myalgic encephalomyelitis frequently meet the criteria for one or more other conditions including: postural orthostatic tachychardia syndrome and other forms of orthostatic intolerance;[4] mast cell activation syndrome;[5] Ehlers-Danlos syndrome;[6] fibromyalgia;[2] endometriosis;[7] and a variety of autoimmune diseases.[2] It is not yet known whether these are true co-morbidities that share underlying genetic or environment risk factors, or if they are artifacts of diagnosis and disease definition.

Canadian Consensus Criteria[edit | edit source]

The Canadian Consensus Criteria recognizes the following comorbidities for ME/CFS: fibromyalgia, myofascial pain syndrome (MPS), temporomandibular joint syndrome (TMJ), irritable bowel syndrome (IBS), interstitial cystitis, irritable bladder syndrome, Raynaud's phenomenon, prolapsed mitral valve, depression, migraine, allergies, multiple chemical sensitivities (MCS), Hashimoto's thyroiditis, and sicca syndrome (Sjögren's syndrome).[2]

Preceding conditions[edit | edit source]

Conditions that begin many years before ME/CFS but then become associated with it, such as irritable bowel syndrome, migraines and depression, are regarded as more loosely associated. ME/CFS and fibromyalgia are regarded by the Canadian Consensus Criteria as often closely connected overlapping syndromes.[2]

International Consensus Criteria[edit | edit source]

The primer for the International Consensus Criteria for myalgic encephalomyelitis, which is based on the earlier Canadian Consensus Criteria gives the following comorbidities: myofascial pain syndrome, temporomandibular joint syndrome (TMJ), interstitial cystitis, Raynaud's phenomenon, prolapsed mitral valve, irritable bladder syndrome, Hashimoto's thyroiditis, sicca syndrome (Sjögren's syndrome), secondary depression, allergies, and multiple chemical sensitivities. Fibromyalgia (FMS) is considered "an overlap condition."

Preceding conditions[edit | edit source]

Irritable bowel syndrome and migraine "may precede ME and then become associated with it."[3]

Theories[edit | edit source]

RCCX Theory

Epidemiology[edit | edit source]

Percentage of ME/CFS patients
POTS 10-70%
hEDS 20%[8]
Fibromyalgia 67%[8]
Percentage of patients in row X who also meet the diagnostic criteria for column Y
ME/CFS POTS Orthostatic intolerance

(all types)

MCAS Fibromyalgia hEDS
ME/CFS * 10-70% 67%[8] 20%[8]
POTS 64%[9] * 31%[10]
Fibromyalgia *
hEDS 74%[11][12] to 78%[13] *

Clinical perspectives[edit | edit source]

  • In “The Nightingale Research Foundation Definition of Myalgic Encephalomyelitis (M.E.),”[14] ME physician Byron Hyde has describes the relationship between ME, POTS/dyaustonomia, and EDS in terms of disease severity:
    • “Patients with dysautonomia and/or POTS dysfunctions invariably demonstrated hypoperfusion in the operculum area overlying the insular cortex as in the above patient, suggesting an insular cortex injury in our dysautonomia patients.”
    • “Patients with pre-existing or newly-discovered (a) Ehlers-Danlos Hypermobility Syndrome, (b) Collagen diseases... are among the most disabled patients we have seen.”
  • A case series by Peter Rowe of adolescents referred to his clinic found 12 patients who also met the criteria for Ehlers-Danlos Syndrome and had orthostatic intolerance (postural orthostatic tachycardia or neurally-mediated hypotension). He concluded that “Among patients with CFS and orthostatic intolerance, a subset also has EDS.”[15]
  • At a two-day physician summit in Salt Lake City, Utah March 2018, physicians discussed the relationship between “Chronic Fatigue Syndrome” and mast cell activation syndrome.[16]
    • David Kaufman: "ME/CFS is a descriptive diagnosis of a bunch of symptoms, but it says nothing about what's causing the symptoms, which is probably part of the reason it's so hard for it to get recognition. So, the question becomes, What other pathology is driving this illness and making the person feel so ill? I think mast cell activation is one of those drivers, whether cause, effect, or perpetuator, I don't know."
    • Charles Lapp: "I see a lot of this. I think it's one of the many overlap syndromes that we've been missing for years."
    • Susan Levine: "I suspect 50% to 60% of ME/CFS patients have it. It's a very new concept."...In Levine's experience, MCAS often manifests in patients being unable to tolerate certain foods or medications. "If we can reduce the mast cell problem, we can facilitate taking other drugs to treat ME/CFS," she said. However, she also cautioned, "It's going to be a subset, not all ME/CFS patients."

Studies and collaborations[edit | edit source]

Research findings[edit | edit source]

Recent research has focused on the possible relationships between EDS, POTS, and MCAS. In particular, these disorders were associated in a sample of 25 families.

Findings ME/CFS POTS MCAS Fibromyalgia hEDS
Central nervous system
Ventricular lactate increased[18][19][20][21]
Grey matter
White matter
Intracranial hypertension Present in a subset[22]
Autonomic nervous system
Small fiber peripheral neuropathy 37.5%[23] 30-50%[24][25][26] 100%[27]
Incidence of POTS 11-70% 100%
Incidence of NMH
Incidence of OI 57%[28]
Musculoskeletal system
mitochondria mitochondrial abnormalities found via muscle biopsy including: mitochondrial degeneration,[29] deletions of mitochondrial DNA,[30][31] the reduction of mitochondrial activity[30]
Cell & metabolism
Lipid raft decreased sphingolipids and glycosphingolipids, building blocks of lipid rafts.[33] autoimmunoreactive IgGs to lipid raft proteins in the heart.[34]
Immune system
Acetylcholine receptor autoantibodies 29% 24%
Other autoantibodies elevated anti-cholinergic muscarinic, Β-adrenergic,[35] phosphatidylinositol[36] and serotonin[37] antibodies
mast cells increased mast cell populations[38]
natural killer cells Natural killer cell function is reduced[39][40]
Cardiovascular system
Preload failure Yes Yes
Low blood volume Yes Yes Yes
Gastrointestinal system
TPSAB1 Unknown Mutation found in a sample of 35 families[41] Mutation found in a sample of 35 families[41] Unknown Mutation found in a sample of 35 families[41]

Diagnoses that are symptoms of ME/CFS[edit | edit source]

A number of illnesses and diseases are not regarded as true comorbidities, but are so common that they classed as diagnostic signs and symptoms instead:

Symptoms that are also a diagnosis include:

See also[edit | edit source]

References[edit | edit source]

  1. "Definition of COMORBID". Merriam-Webster. Retrieved May 5, 2019.
  2. 2.0 2.1 2.2 2.3 2.4 Carruthers, Bruce M.; Jain, Anil Kumar; De Meirleir, Kenny L.; Peterson, Daniel L.; Klimas, Nancy G.; Lerner, A. Martin; Bested, Alison C.; Flor-Henry, Pierre; Joshi, Pradip; Powles, AC Peter; Sherkey, Jeffrey A.; van de Sande, Marjorie I. (2003), "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols" (PDF), Journal of Chronic Fatigue Syndrome, 11 (2): 13, doi:10.1300/J092v11n01_02
  3. 3.0 3.1 Carruthers, BM; van de Sande, MI; De Meirleir, KL; Klimas, NG; Broderick, G; Mitchell, T; Staines, D; Powles, ACP; Speight, N; Vallings, R; Bateman, L; Bell, DS; Carlo-Stella, N; Chia, J; Darragh, A; Gerken, A; Jo, D; Lewis, DP; Light, AR; Light, KC; Marshall-Gradisnik, S; McLaren-Howard, J; Mena, I; Miwa, K; Murovska, M; Stevens, SR (2012), Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners (PDF), p. 12, ISBN 978-0-9739335-3-6
  4. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington,D.C.: National Academies Press. March 16, 2015. doi:10.17226/19012. ISBN 978-0-309-31689-7.
  5. Rönnberg, E; Calounova, G; Pejler, G (June 2017). "Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients". Asian Pac J Allergy Immunol. 35 (2): 75–81.
  6. Rowe, Peter C.; Barron, Diana F.; Calkins, Hugh; Maumenee, Irene H.; Tong, Patrick Y.; Geraghty, Michael T. (October 1, 1999). "Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome". The Journal of Pediatrics. 135 (4): 494–499. doi:10.1016/S0022-3476(99)70173-3. ISSN 0022-3476.
  7. Boneva, Roumiana S.; Lin, Jin-Mann S.; Wieser, Friedrich; Nater, Urs M.; Ditzen, Beate; Taylor, Robert N.; Unger, Elizabeth R. (April 2018). "Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data from a CFS Case-Control study". Frontiers in Pediatrics. doi:10.3389/fped.2019.00195.
  8. 8.0 8.1 8.2 8.3 "Bragee Bertilson et al. - ME CFS and Intracranial Hypertension". Retrieved February 5, 2020.
  9. Okamoto, Luis E.; Raj, Satish R.; Peltier, Amanda; Gamboa, Alfredo; Shibao, Cyndya; Diedrich, André; Black, Bonnie K.; Robertson, David; Biaggioni, Italo (February 1, 2012). "Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes". Clinical Science (London, England : 1979). 122 (Pt 4): 183–192. doi:10.1042/CS20110200. ISSN 0143-5221. PMID 21906029.
  10. Miller, Amanda J.; Stiles, Lauren E.; Sheehan, Timothy; Bascom, Rebecca; Levy, Howard P.; Francomano, Clair A.; Arnold, Amy C. (March 1, 2020). "Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome". Autonomic Neuroscience. 224: 102637. doi:10.1016/j.autneu.2020.102637. ISSN 1566-0702.
  11. Malfait, Fransiska; Calders, Patrick; De Paepe, Anne; De Mits, Sophie; Da Silva, Hellen; Peersman, Wim; De Backer, Tine; Rombaut, Lies; De Wandele, Inge (August 1, 2016). "Orthostatic intolerance and fatigue in the hypermobility type of Ehlers-Danlos Syndrome". Rheumatology. 55 (8): 1412–1420. doi:10.1093/rheumatology/kew032. ISSN 1462-0324.
  12. De Wandele, Inge; Rombaut, Lies; Leybaert, Luc; Van de Borne, Philippe; De Backer, Tine; Malfait, Fransiska; De Paepe, Anne; Calders, Patrick (August 1, 2014). "Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers–Danlos syndrome". Seminars in Arthritis and Rheumatism. 44 (1): 93–100. doi:10.1016/j.semarthrit.2013.12.006. ISSN 0049-0172.
  13. Gazit, Yael; Nahir, A. Menahem; Grahame, Rodney; Jacob, Giris (July 1, 2003). "Dysautonomia in the joint hypermobility syndrome". The American Journal of Medicine. 115 (1): 33–40. doi:10.1016/S0002-9343(03)00235-3. ISSN 0002-9343.
  14. Hyde, Byron. The Nightingale Research Foundation Definition of Myalgic Encephalomyelitis (M.E.) (PDF). Cornell University.
  15. Rowe, Peter C.; Barron, Diana F.; Calkins, Hugh; Maumenee, Irene H.; Tong, Patrick Y.; Geraghty, Michael T. (October 1, 1999). "Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome". The Journal of Pediatrics. 135 (4): 494–499. doi:10.1016/S0022-3476(99)70173-3. ISSN 0022-3476.
  16. "Medscape Log In". Medscape. Retrieved September 25, 2018.
  17. "Molecular Underpinnings of ME/CFS Explored at the Open Medicine Foundation Symposium | Open Medicine Foundation". Open Medicine Foundation. September 9, 2017. Retrieved September 25, 2018.
  18. Mathew, Sanjay J.; Mao, Xiangling; Keegan, Kathryn A.; Levine, Susan M.; Smith, Eric L.P.; Heier, Linda A.; Otcheretko, Viktor; Coplan, Jeremy D.; Shungu, Dikoma C. (April 2009). "Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: anin vivo3.0 T1H MRS imaging study". NMR in Biomedicine. 22 (3): 251–258. doi:10.1002/nbm.1315. ISSN 0952-3480.
  19. Murrough, James W.; Mao, Xiangling; Collins, Katherine A.; Kelly, Chris; Andrade, Gizely; Nestadt, Paul; Levine, Susan M.; Mathew, Sanjay J.; Shungu, Dikoma C. (July 2010). "Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder". NMR in biomedicine. 23 (6): 643–650. doi:10.1002/nbm.1512. ISSN 1099-1492. PMID 20661876.
  20. Shungu, Dikoma C.; Weiduschat, Nora; Murrough, James W.; Mao, Xiangling; Pillemer, Sarah; Dyke, Jonathan P.; Medow, Marvin S.; Natelson, Benjamin H.; Stewart, Julian M. (September 2012). "Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology". NMR in biomedicine. 25 (9): 1073–1087. doi:10.1002/nbm.2772. ISSN 1099-1492. PMC 3896084. PMID 22281935.
  21. Natelson, Benjamin H.; Vu, Diana; Coplan, Jeremy D.; Mao, Xiangling; Blate, Michelle; Kang, Guoxin; Soto, Eli; Kapusuz, Tolga; Shungu, Dikoma C. (January 2, 2017). "Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia". Fatigue: Biomedicine, Health & Behavior. 5 (1): 15–20. doi:10.1080/21641846.2017.1280114. ISSN 2164-1846. PMC 5754037. PMID 29308330.
  22. Higgins, Nicholas; Pickard, John; Lever, Andrew (November 21, 2013). "Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study". JRSM Short Reports. 4 (12): 204253331350792. doi:10.1177/2042533313507920. ISSN 2042-5333.
  23. Gibbons, Christopher H.; Bonyhay, Istvan; Benson, Adam; Wang, Ningshan; Freeman, Roy (December 27, 2013). "Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome". PLoS ONE. 8 (12): e84716. doi:10.1371/journal.pone.0084716. ISSN 1932-6203. PMC 3874039. PMID 24386408.
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  26. Levine, ToddD.; Saperstein, David S. (December 24, 2014). "Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients". Clinical Rheumatology. 34 (3): 413–417. doi:10.1007/s10067-014-2850-5. ISSN 0770-3198. PMC 4348533. PMID 25535201.
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  32. Albrecht, Robert (March 21, 1964). "Epidemic Neuromyasthenia Outbreak in a Convent in New York State". Journal of the American Medical Association. 187: 904–907.
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  34. "Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome". Translational Research. 162 (1): 34–44. July 1, 2013. doi:10.1016/j.trsl.2013.03.002. ISSN 1931-5244.
  35. Loebel, Madlen; Grabowski, Patricia; Heidecke, Harald; Bauer, Sandra; Hanitsch, Leif G.; Wittke, Kirsten; Meisel, Christian; Reinke, Petra; Volk, Hans-Dieter (February 2016). "Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome". Brain, Behavior, and Immunity. 52: 32–39. doi:10.1016/j.bbi.2015.09.013. ISSN 1090-2139. PMID 26399744.
  36. Maes, Michael; Mihaylova, Ivanka; Leunis, Jean-Claude (December 2007). "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". Neuro Endocrinology Letters. 28 (6): 861–867. ISSN 0172-780X. PMID 18063934.
  37. Maes, Michael; Ringel, Karl; Kubera, Marta; Anderson, George; Morris, Gerwyn; Galecki, Piotr; Geffard, Michel (September 5, 2013). "In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation". Journal of Affective Disorders. 150 (2): 223–230. doi:10.1016/j.jad.2013.03.029. ISSN 1573-2517. PMID 23664637.
  38. Rönnberg, E; Calounova, G; Pejler, G (June 2017). "Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients". Asian Pac J Allergy Immunol. 35 (2): 75–81.
  39. Brenu, Ekua Weba; Huth, Teilah K.; Hardcastle, Sharni L.; Fuller, Kirsty; Kaur, Manprit; Johnston, Samantha; Ramos, Sandra B.; Staines, Don R.; Marshall-Gradisnik, Sonya M. (April 2014). "Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis". International Immunology. 26 (4): 233–242. doi:10.1093/intimm/dxt068. ISSN 1460-2377. PMID 24343819.
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  41. 41.0 41.1 41.2 Lyons, Jonathan J.; Yu, Xiaomin; Hughes, Jason D.; Le, Quang T.; Jamil, Ali; Bai, Yun; Ho, Nancy; Zhao, Ming; Liu, Yihui (December 2016). "Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number". Nature Genetics. 48 (12): 1564–1569. doi:10.1038/ng.3696. ISSN 1546-1718. PMC 5397297. PMID 27749843.