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Christina Sarris
2012 Medical Student
Scholarship Winner
Enumerate the various possible causes of Chronic Fatigue Syndrome (also referred to as Myalgic Encephalomyelitis). Discuss the evidence for and against these causes.
Introduction
Feelings of fatigue are common complaints in the general population, yet in the majority of cases, the fatigue is self-limited or has a known cause. Chronic Fatigue Syndrome, also referred to as Myalgic Encephalomyelitis, is a frustrating medical condition characterized by unexplained persistent fatigue that results in significant deficits in ones daily social, educational, and occupational activities. When those affected first become symptomatic, the main complaint is generally an abrupt onset of impairing fatigue that hinders daily activity. HYPERLINK \l "_ENREF_1" \o "Bennett, 2012 #180" ADDIN EN.CITE Bennett20121801801806Bennett, Robert M.Goldman: Goldman's Cecil Medicine242012Philadelphia, PAElsevier1 Symptoms include sore throat, muscle and joint pain, headaches, and sleep that fails to cause one to feel refreshed. Chronic fatigue syndrome is only diagnosed when other medical conditions that may explain the presence of the fatigue are ruled out. HYPERLINK \l "_ENREF_1" \o "Bennett, 2012 #180" ADDIN EN.CITE Bennett20121801801806Bennett, Robert M.Goldman: Goldman's Cecil Medicine242012Philadelphia, PAElsevier1
Frustratingly, the cause of Chronic Fatigue Syndrome is still poorly understood and widely speculated. It has proven to be very difficult to identify a single cause, and much of the current scientific thought suggests that Chronic Fatigue Syndrome is multifactorial, with both environmental and genetic components playing a role in manifestation of the disease symptoms. HYPERLINK \l "_ENREF_2" \o "Mandell, 2010 #181" ADDIN EN.CITE Mandell20101811811816Mandell, Gerald L.Principles and Practice of Infectious Disease12010Philadelphia, PAElsveir2 One of the major obstacles in elucidating the causes of Chronic Fatigue Syndrome is the difficulty of finding a large, homogeneous group of patients who fit the current definition of the disease. One can imagine that for a patient suffering from such debilitating symptoms, with a poorly understood cause, it can be a very trying and difficult experience. In the world of twenty-first century medicine and science, it is often expected that we have the answers to why someone would suffer with a disease such as this. When a patient is told that the answer is unknown, it can be extremely disheartening and frustrating. Thus, it is critical that medical providers, as well as the general population, become aware of the challenges associated with Chronic Fatigue Syndrome so that compassionate care can be provided with a firm knowledge of the reality those afflicted endure on a daily basis. As more become aware of what Chronic Fatigue Syndrome entails, as well as informed of the promising research currently being conducted, the future of those suffering with the disease can be improved substantially. It is only with increased dissemination of the current knowledge regarding Chronic Fatigue Syndrome that we can hope to make progress towards greater understanding and potential treatments. In this review, the current ideas surrounding the etiology and pathogenesis of Chronic Fatigue Syndrome are discussed.
Infectious Agents and Chronic Fatigue Syndrome
Speculation over the true cause of the disease has existed since the early 1980s. In many cases of chronic fatigue, patients have become symptomatic after combating a specific infectious disease. Thus, infectious agents have been suggested in many instances, yet there remains no single pathogen that can be identified in a significant proportion of cases. In 1985, two large studies of patients with significant chronic fatigue and other symptoms were reported to have elevated antibody titers against Epstein-Barr virus (EBV) in comparison to healthy controls ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK \l "_ENREF_3" \o "Straus, 1985 #219" 3, HYPERLINK \l "_ENREF_4" \o "Jones, 1985 #183" 4, and thus it was suggested that chronic fatigue syndrome was actually caused by chronic mononucleosis infection. This idea failed to persist as further studies did not confirm the role of EBV in cases of chronic fatigue syndrome. HYPERLINK \l "_ENREF_5" \o "Mawle, 1995 #230" ADDIN EN.CITE ADDIN EN.CITE.DATA 5-7
Over the years, Chronic Fatigue Syndrome has been linked to a wide variety of other disease-causing agents such as enteroviruses, cytomegalovirus, Candida albicans, Borrelia burgdorferi, and human herpesvirus. HYPERLINK \l "_ENREF_2" \o "Mandell, 2010 #181" ADDIN EN.CITE Mandell20101811811816Mandell, Gerald L.Principles and Practice of Infectious Disease12010Philadelphia, PAElsveir2 Evidence implicating these agents in the disease etiology has not been substantiated in subsequent studies. In a study of 22 monozygotic twin pairs, there was no difference in plasma levels of antibodies to human herpesvirus (HHV)-6, HHV-8, cytomegalovirus, and EBV between the group of twins with Chronic Fatigue Syndrome and the healthy twins. HYPERLINK \l "_ENREF_8" \o "Koelle, 2002 #103" ADDIN EN.CITE ADDIN EN.CITE.DATA 8 Enterovirus VP1, RNA and non-cytopathic viruses have been found in stomach biopsy specimens of Chronic Fatigue Syndrome patients, suggesting that a significant subset of patients may have a chronic enteroviral infection. HYPERLINK \l "_ENREF_9" \o "Chia, 2008 #50" ADDIN EN.CITE Chia200850505017Chia, J. K.Chia, A. Y.EV Med Research, Lomita, California 90717, USA. evmed@sbcglobal.netChronic fatigue syndrome is associated with chronic enterovirus infection of the stomachJ Clin PatholJournal of clinical pathologyJ Clin PatholJournal of clinical pathologyJ Clin PatholJournal of clinical pathology43-86112007/09/18Capsid Proteins/analysisChronic DiseaseEnterovirus/genetics/*isolation & purificationEnterovirus Infections/*complicationsFatigue Syndrome, Chronic/*virologyFemaleHumansImmunoenzyme TechniquesMaleRNA, Viral/analysisStomach Diseases/*complications/virologyTissue Culture Techniques2008Jan1472-4146 (Electronic)
0021-9746 (Linking)17872383Research Support, Non-U.S. Gov'thttp://www.ncbi.nlm.nih.gov/pubmed/1787238310.1136/jcp.2007.050054eng9 Giardia enteritis appears to have caused an outbreak of Chronic Fatigue Syndrome in 5% of those infected in a large community. HYPERLINK \l "_ENREF_10" \o "Naess, 2012 #139" ADDIN EN.CITE ADDIN EN.CITE.DATA 10 It has also been estimated that postinfectious fatigue occurs at a rate of 12% following infection with EBV, Q fever, or Ross River virus HYPERLINK \l "_ENREF_11" \o "Hickie, 2006 #233" ADDIN EN.CITE ADDIN EN.CITE.DATA 11, and that postinfectious fatigue has symptoms that are clinically indistinguishable from idiopathic cases of fatigue. HYPERLINK \l "_ENREF_12" \o "Buchwald, 1996 #235" ADDIN EN.CITE Buchwald199623523523517Buchwald, D.Umali, J.Pearlman, T.Kith, P.Ashley, R.Wener, M.Department of Medicine, University of Washington, Seattle, USA.Postinfectious chronic fatigue: a distinct syndrome?Clin Infect DisClinical infectious diseases : an official publication of the Infectious Diseases Society of AmericaClin Infect DisClinical infectious diseases : an official publication of the Infectious Diseases Society of AmericaClin Infect DisClinical infectious diseases : an official publication of the Infectious Diseases Society of America385-72321996/08/01Fatigue Syndrome, Chronic/*physiopathologyHumans1996Aug1058-4838 (Print)
1058-4838 (Linking)8842279Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.http://www.ncbi.nlm.nih.gov/pubmed/8842279eng12 Because of such common manifestations of fatigue symptoms following numerous infectious diseases, it has been suggested that Chronic Fatigue Syndrome is a product of a variety of types of infections rather than a disease with a single specific etiology.
Recently in the research of infectious agents as cause of Chronic Fatigue Syndrome were the 2009 studies suggesting that most cases were associated with a newly described gamma retrovirus, xenotropic murine leukemia virus-related virus (XMRV). HYPERLINK \l "_ENREF_13" \o "Lombardi, 2009 #253" ADDIN EN.CITE ADDIN EN.CITE.DATA 13 A study detected the virus in 67% of patients suffering, compared with only 3.7% in healthy controls. There was much excitement surrounding this supposed breakthrough in the frustrating disease, but soon after publication concerns arose. Further studies could not find any evidence of XMRV infection in the same samples tested in the 2009 study, and it was suggested that the XMRV virus arose as the consequence of recombination between two mouse proviruses years following the first documented description of Chronic Fatigue Syndrome. ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK \l "_ENREF_14" \o "Knox, 2011 #254" 14, HYPERLINK \l "_ENREF_15" \o "Paprotka, 2011 #255" 15 As much excitement surrounded XMRV and its role in the disease etiology, the heated debate stressed the importance of full scientific validation in the search for understanding of Chronic Fatigue Syndrome. HYPERLINK \l "_ENREF_16" \o "Etzioni, 2011 #65" ADDIN EN.CITE Etzioni201165656517Etzioni, A.Chronic fatigue syndrome: still a long way to goIsr Med Assoc JThe Israel Medical Association journal : IMAJIsr Med Assoc JThe Israel Medical Association journal : IMAJIsr Med Assoc JThe Israel Medical Association journal : IMAJ76113122012/02/16Biomedical ResearchFatigue Syndrome, Chronic/*etiologyHumansResearch Design*Xenotropic murine leukemia virus-related virus2011Dec1565-1088 (Print)22332448Editorialhttp://www.ncbi.nlm.nih.gov/pubmed/22332448eng16
Genetics and Chronic Fatigue Syndrome
Possible genetic predisposition to Chronic Fatigue Syndrome has been investigated. Using the CDC guidelines for diagnosis of Chronic Fatigue Syndrome, a study demonstrated a concordance of 38% in monozygotic twins versus 11% in dizygotic twins. HYPERLINK \l "_ENREF_17" \o "Buchwald, 2001 #267" ADDIN EN.CITE Buchwald200126726726717Buchwald, D.Herrell, R.Ashton, S.Belcourt, M.Schmaling, K.Sullivan, P.Neale, M.Goldberg, J.Department of Medicine, University of Washington, Seattle, WA, USA. dedra@u.washington.eduA twin study of chronic fatiguePsychosom MedPsychosomatic medicinePsychosom MedPsychosomatic medicinePsychosom MedPsychosomatic medicine936-436362001/11/24AdultFatigue Syndrome, Chronic/epidemiology/*genetics/immunologyFemaleHLA Antigens/immunologyHumansMalePrevalenceTwins/*psychology2001Nov-Dec0033-3174 (Print)
0033-3174 (Linking)11719632Research Support, U.S. Gov't, P.H.S.
Twin Studyhttp://www.ncbi.nlm.nih.gov/pubmed/11719632eng17 Several genes have been implicated in those affected with Chronic Fatigue Syndrome in recent studies. ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK \l "_ENREF_18" \o "Kerr, 2008 #270" 18, HYPERLINK \l "_ENREF_19" \o "Kerr, 2008 #271" 19 NMR metabolic profiling of a group of patients with Chronic Fatigue Syndrome has demonstrated a significant reduction of glutamine and ornithine in the blood of those affected, suggesting a possible disturbance in amino acid and nitrogen metabolism in disease etiology. HYPERLINK \l "_ENREF_20" \o "Armstrong, 2012 #36" ADDIN EN.CITE Armstrong201236363617Armstrong, C. W.McGregor, N. R.Sheedy, J. R.Buttfield, I.Butt, H. L.Gooley, P. R.Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndromeClin Chim ActaClinica chimica acta; international journal of clinical chemistryClin Chim ActaClinica chimica acta; international journal of clinical chemistryClin Chim ActaClinica chimica acta; international journal of clinical chemistry1525-153141319-202012/06/262012Jun 211873-3492 (Electronic)
0009-8981 (Linking)22728138http://www.ncbi.nlm.nih.gov/pubmed/2272813810.1016/j.cca.2012.06.022Eng20 Cifuentes and Barreto identified a reliable profile of single nucleotide polymorphisms associated with Chronic Fatigue Syndrome, suggesting markers for genetic predisposition to the disease. HYPERLINK \l "_ENREF_21" \o "Cifuentes, 2011 #64" ADDIN EN.CITE Cifuentes201164646417Cifuentes, R. A.Barreto, E.Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogota, D.C, Colombia.Supervised selection of single nucleotide polymorphisms in chronic fatigue sindromeBiomedicaBiomedica : revista del Instituto Nacional de SaludBiomedicaBiomedica : revista del Instituto Nacional de SaludBiomedicaBiomedica : revista del Instituto Nacional de Salud613-213142012/06/082011Dec0120-4157 (Print)
0120-4157 (Linking)22674373http://www.ncbi.nlm.nih.gov/pubmed/2267437310.1590/S0120-41572011000400017eng21 Such findings suggest a genetic component to Chronic Fatigue Syndrome, further highlighting the disease as a multifactorial syndrome. Large-scale genomic studies will prove invaluable to further research in the genetics of Chronic Fatigue Syndrome in the near future.
Immunology, Neurophysiology, and Chronic Fatigue Syndrome
The associations that have been made between Chronic Fatigue Syndrome and infectious agents have caused attention to shift towards an immunological basis for the condition. Decreased cytotoxic activity has been shown in patients in many studies. HYPERLINK \l "_ENREF_22" \o "Klimas, 1990 #99" ADDIN EN.CITE ADDIN EN.CITE.DATA 22-24 It has been demonstrated that those with Chronic Fatigue Syndrome may have deficient natural killer cell activation and effector capacity. HYPERLINK \l "_ENREF_25" \o "Bassi, 2008 #241" ADDIN EN.CITE ADDIN EN.CITE.DATA 25-27 This suggests an underlying immunodeficiency in those affected that would thus cause a more severe inflammatory response to infectious agents. Such an inflammatory response may result in presentation with Chronic Fatigue Syndrome. Furthermore, Zhang et al. demonstrated that the expression of TGF-B1 in peripheral blood mononuclear cells is significantly elevated in patients with Chronic Fatigue Syndrome. HYPERLINK \l "_ENREF_28" \o "Zhang, 2011 #165" ADDIN EN.CITE ADDIN EN.CITE.DATA 28
Notably, several immune-related microRNAs have been implicated as potential biomarkers for Chronic Fatigue Syndrome, as they play a role in regulating natural killer cells and CD8+T cell related lytic proteins, receptors, and cytotoxic activity. HYPERLINK \l "_ENREF_29" \o "Brenu, 2012 #43" ADDIN EN.CITE Brenu201243434317Brenu, E. W.Ashton, K. J.van Driel, M.Staines, D. R.Peterson, D.Atkinson, G. M.Marshall-Gradisnik, S. M.Faculty of Health Science and Medicine, Population Health and Neuroimmunology Unit, Bond University, Robina, Queensland, Australia; Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia.Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic EncephalomyelitisJ Affect DisordJournal of affective disordersJ Affect DisordJournal of affective disordersJ Affect DisordJournal of affective disorders2012/05/112012May 71573-2517 (Electronic)
0165-0327 (Linking)22572093http://www.ncbi.nlm.nih.gov/pubmed/2257209310.1016/j.jad.2012.03.037Eng29 Changes in the microRNAs of these cells may disrupt proper functioning in immune response, thus leading to disease symptoms.
Because Chronic Fatigue Syndrome generally involves neuropsychological symptoms and alterations in hormone levels regulated by the hypothalamus, many feel that the central nervous system is the main site involved in the pathophysiology of the disease. Regions of decreased cerebral blood flow were observed in patients with Chronic Fatigue Syndrome HYPERLINK \l "_ENREF_30" \o "Schwartz, 1994 #276" ADDIN EN.CITE ADDIN EN.CITE.DATA 30, however these findings were not confirmed in subsequent studies. HYPERLINK \l "_ENREF_31" \o "Lewis, 2001 #282" ADDIN EN.CITE ADDIN EN.CITE.DATA 31 Dysfunction of the hypothalamic-pituitary-adrenal axis has also been implicated, with reported studies of exaggerated adrenal responsiveness to corticotropin infusions and lower urinary free cortisol levels in those affected. HYPERLINK \l "_ENREF_32" \o "Demitrack, 1997 #297" ADDIN EN.CITE Demitrack199729729729717Demitrack, M. A.Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.Neuroendocrine correlates of chronic fatigue syndrome: a brief reviewJ Psychiatr ResJournal of psychiatric researchJ Psychiatr ResJournal of psychiatric researchJ Psychiatr ResJournal of psychiatric research69-823111997/01/01Adrenocorticotropic Hormone/blood/urineAdultFatigue Syndrome, Chronic/diagnosis/*etiologyFemaleFibromyalgia/diagnosisHumansHydrocortisone/blood/urineHypothalamo-Hypophyseal System/*physiologyMalePituitary-Adrenal System/*physiologyProlactin/blood1997Jan-Feb0022-3956 (Print)
0022-3956 (Linking)9201649Comparative Studyhttp://www.ncbi.nlm.nih.gov/pubmed/9201649eng32
It is evident that both immunologic and neurologic factors may be involved in the pathogenesis of Chronic Fatigue Syndrome. Some argue that Chronic Fatigue Syndrome etiology lies in the immunophysiology of the central nervous system, resulting from inflammatory events in the brain. HYPERLINK \l "_ENREF_33" \o "Arnett, 2011 #41" ADDIN EN.CITE Arnett201141414117Arnett, S. V.Alleva, L. M.Korossy-Horwood, R.Clark, I. A.Research School of Biology, Australian National University, Australia. simon.arnett@anu.edu.auChronic fatigue syndrome--a neuroimmunological modelMed HypothesesMedical hypothesesMed HypothesesMedical hypothesesMed HypothesesMedical hypotheses77-837712011/04/09Central Nervous System/*physiopathologyFatigue Syndrome, Chronic/*immunology/physiopathologyHumans*Models, Biological2011Jul1532-2777 (Electronic)
0306-9877 (Linking)21474251http://www.ncbi.nlm.nih.gov/pubmed/2147425110.1016/j.mehy.2011.03.030eng33 Natelson et al. demonstrated that IL-8 and IL-10 were significantly elevated in the cerebrospinal fluid collected from patients with Chronic Fatigue Syndrome. HYPERLINK \l "_ENREF_34" \o "Natelson, 2005 #248" ADDIN EN.CITE ADDIN EN.CITE.DATA 34 A variety of immunological and neurological abnormalities have been reported in patients with Chronic Fatigue Syndrome, including mitochondrial dysfunctions, abnormalities in proinflammatory cytokines, brain pathology, and autonomic disturbances. Morris and Maes HYPERLINK \l "_ENREF_35" \o "Morris, 2012 #107" ADDIN EN.CITE Morris201210710710717Morris, G.Maes, M.Tir Na Nog, Pembrey, Llanelli, UK.A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndromeMetab Brain DisMetabolic brain diseaseMetab Brain DisMetabolic brain diseaseMetab Brain DisMetabolic brain disease2012/06/222012Jun 211573-7365 (Electronic)
0885-7490 (Linking)22718491http://www.ncbi.nlm.nih.gov/pubmed/2271849110.1007/s11011-012-9324-8Eng35 propose that initial infection and immune activation caused by a variety of infectious agents leads to a state of chronic peripheral immune activation guided by activated oxidative and nitrosative stress pathways. Such a response produces mitochondrial damage, and subsequent ATP deficits together with inflammation are suggested to cause the symptoms of Chronic Fatigue Syndrome. HYPERLINK \l "_ENREF_35" \o "Morris, 2012 #107" ADDIN EN.CITE Morris201210710710717Morris, G.Maes, M.Tir Na Nog, Pembrey, Llanelli, UK.A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndromeMetab Brain DisMetabolic brain diseaseMetab Brain DisMetabolic brain diseaseMetab Brain DisMetabolic brain disease2012/06/222012Jun 211573-7365 (Electronic)
0885-7490 (Linking)22718491http://www.ncbi.nlm.nih.gov/pubmed/2271849110.1007/s11011-012-9324-8Eng35 A variety of neuroimmune models for the disease have been proposed very recently, and such studies are encouraging as the etiology of this complex disease becomes elucidated.
Conclusion
While this review does not provide a single, concrete cause for the pathogenesis of Chronic Fatigue Syndrome, it is evident that a tremendous amount of new and promising research is currently taking place in the field. The cause(s) of the disease are most likely multiple and complex, involving delicate interactions among a variety of systems within the body and the environment. With such enthusiasm for understanding the etiology of this debilitating disease, it is unquestionable that further investigations will lead us closer to firm knowledge of the pathogenesis and treatment options for those affected by Chronic Fatigue Syndrome. In the meantime, it remains paramount that physicians, as well as the general public, be made aware of the signs, symptoms, and implications of Chronic Fatigue Syndrome in order to best aid those affected in a compassionate and knowledgeable manner.
References
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