Although ME/CFS has inspired thousands of scientific and popular publications, its cause remains, as yet, unidentified. The debate surrounding the pathogenesis of ME/CFS has raged for decades. Some support the idea that a single pathogen (e.g a virus) produces the illness, while others adhere to the idea that ME/CFS is environmental, the result of exposure to a number of toxins that damage the nervous and immune systems. Each of these theories generates its own research, its own spate of tests, and its own treatment protocols.
ME/CFS is a complex illness, which makes the search for a cause laden with difficulties. However, enough is known of the illness to establish some basic parameters. Any etiological model for ME/CFS must take into account the following: 1) multisystem symptoms, 2) chronic illness, and 3) outbreaks.
While most researchers tend to focus on 1 and 2, they often forget the infectious aspect of ME/CFS. Ultimately, any theory attempting to explain how ME/CFS occurs in an individual must also account for why it occurs in groups.
Dr. Bell describes the pathogenesis of ME/CFS as the “1-2 punch.” The first punch would be the cause, which can eventually become an occult, or hidden infection, the second is the “trigger.” The first exposure to a pathogen weakens the host, the second actually makes the person ill. There is considerable support for the idea of occult infection in many disease processes, particularly in persistent viral and bacterial infections (such as Lyme).
The predominant theory in the U.S. is that ME/CFS is caused by a virus. This theory is supported by history (ME/CFS epidemics have often followed polio epidemics), incidence (correlation with a triggering viral illness), flu-like symptoms (swollen lymph nodes, malaise, sore throat), and similarities to other ailments with viral etiologies, notably mononucleosis and post-polio syndrome. A viral cause is supported by a substantial body of primary research. In the mid-1980s, Dr. Cheney and Dr. Peterson, the two clinicians who reported the 1984 outbreak in Incline Village, Nevada, found high titers of Epstein-Barr virus (EBV) in their patients. At the time, they believed the illness was caused by chronic activation of this virus alone. However, the presence of EBV titers in most of the healthy population, as well as high titers of many other viruses in the ME/CFS population, eliminated EBV as the primary culprit. Nevertheless, the idea that a herpesvirus was at the root of the illness has persisted, primarily because the herpesviruses are known to establish latency – that is, they are never completely eradicated by the immune system.
Dr. Martin Lerner’s research has shown that multiple herpesvirus strains can affect what appear to be healthy cells, altering their function. In these cases, the host cells are considered “non-permissive,” meaning they don’t permit viral replication. However, what Dr. Lerner found in ME/CFS patients was evidence of cell dysregulation eventually leading to cell apoptosis (death) in non-permissive cells. In short, the damage to these healthy cells was just as profound as the damage to those destroyed by viral replication. (Dr. Richardson also observed this phenomenon in Coxsackie virus infections, in which the function of healthy cells was altered due to nearby viral activity.) Dr. Lerner has supported his position with the evidence of successful treatment. In his practice, he has found that antiviral medications which control herpesviruses (e.g., Valcyte) also eradicate ME/CFS symptoms.
Some researchers believe that because herpesviruses are ubiquitous, their replication is a consequence rather than a cause. These scientists have turned their attention to those viruses that are known to have direct effects on the immune system as well as the ability to use the host’s own DNA to replicate. In 1986 Dr. Michael Holmes, a researcher in New Zealand, found evidence of a retrovirus in ME/CFS patients. This finding was validated by research conducted in 1990 by Dr. Elaine De Freitas of the Wistar Institute in Philadelphia. She found viral fragments of HTLV (human T-lymphotropic virus) in the mitochondria of cells from 30 patients with ME/CFS. None of the 20 controls tested positive for the virus. Dr. De Freitas concluded that her research supported an association between an HTLV-II-like virus and ME/CFS.
Dr. De Freitas’ research was not replicated by the CDC, so her theory of a retroviral etiology was abandoned. However, nearly twenty years later, another retrovirus was discovered in ME/CFS patients. In 2009 the Whittemore Peterson Institute (WPI) announced that a team of researchers had found definitive proof of a retrovirus in ME/CFS patients. The researchers, who hailed from several prestigious labs, including the National Cancer Institute, the Lerner Institute, the Cleveland Clinic, and the Laboratory of Cancer Prevention, identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV) in 68 of 101 patients (67%). The group concluded that their findings “raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.” Like the work of De Freitas, the study could not be replicated. In September 2011, the researchers were compelled to publish a retraction of the original study, which effectively put a halt to XMRV research, as well as any other significant research into a retroviral cause for ME/CFS.
Retroviruses and herpesviruses are not the only viruses that can cause lasting damage. The late Dr. John Richardson, a British physician who treated patients with post-viral syndromes for more than four decades, believed an enterovirus much like the one which causes polio might be at the root of the ME.
Enteroviruses are highly infectious viruses that enter the body through the gastrointestinal (GI) tract and gravitate to the central nervous system, heart and muscle tissues. They are resistant to both stomach acid and bile, which enables them to persist in the GI tract for long periods of time.
To make his case for an enteroviral etiology, Dr. Richardson pointed to the remarkable similarity and incidence of polio-related symptoms and those produced by ME. Dr. Peter Behan and his team of researchers in Glasgow, Scotland, also found indications of a persistent enteroviral infection in about 60% of the ME/CFS patients they tested. Dr. Behan speculated that the virus is a mutated form of poliovirus that attacks the brain rather than the spinal cord, causing a “cascade effect.” This theory fits in well with the historical evidence, as well as epidemiology. (The early outbreaks of ME followed polio epidemics.)
Dr. Chia has also discovered enteroviral infections in ME/CFS patients. Stomach biopsies taken from a group of 165 ME/CFS patients showed persistent active enteroviral infections, in some cases several years after the initial infection was first noted. The degree of viral load matched symptoms to such an extent that the researchers concluded that enteroviral infections might be causal. Dr. Chia tested his hypothesis several years later by following a group of patients who had been admitted to the hospital with acute enteroviral infections. Three of those patients went on to develop ME/CFS.
Other less well-known viruses have also been implicated. In the early 1990s, W. John Martin found evidence of atypical viral infection in the cerebrospinal fluid and brains of several patients who had previously been diagnosed with ME/CFS. The infection was thought to be due to a stealth virus, a class of neurotoxic virus that cause very little inflammation.
Parvovirus B19, a virus that targets red blood cell precursors in bone marrow, has been implicated as well. Follow-up studies of patients with acute parvovirus B19 infections conducted by J.R. Kerr in Great Britain showed that a significant proportion of patients went on to develop both arthritis and ME/CFS. Kerr proposed a genetic flaw that would allow for persistent immune activation – a mechanism which has been explored by many other researchers.
In a paper published in late 1999 in the European Journal of Clinical Microbiology and Infectious Diseases, microbiologist Garth Nicolson demonstrated that multiple species of mycoplasma were present in the blood of patients with ME/CFS (more than 60%). Mycoplasmas are tiny bacteria that lack cell walls, and thus are unaffected by most common antibiotics. Several strains of mycoplasma have been implicated in human diseases:
Mycoplasma pneumoniae can cause walking pneumonia, and Mycoplasma genitalium has been implicated in pelvic inflammatory disease. Mycoplasmas have also been found in AIDS patients and Gulf War Illness patients.
Phillipe Bottero, a French doctor, found that all of his ME/CFS patients tested positive for bacterial infections with rickettsia. The rickettsia are a group of pathogenic tick-borne bacteria responsible for typhus and Rocky Mountain spotted fever, as well as many other diseases. Because they colonize the vascular system, and can therefore travel throughout the body, rickettsial bacteria can cause pneumonia, encephalitis, myocarditis, lesions in the liver, gastrointestinal wall and pancreas, as well as central nervous system inflammation. Dr. Bottero proposed that due to the long survival of rickettsial infection in vascular linings, the resulting vasculitis could produce many of the symptoms common in ME/CFS; 78.5% of Dr. Bottero’s 98 CFS patients improved significantly after treatment with antibiotics.
Cecile Jadin, a Belgian surgeon with a practice in South Africa, also found strong correlations between rickettsial infections and patients diagnosed with ME/CFS. With a single course of tetracycline, Dr. Jadin reversed symptoms in five hundred patients previously diagnosed with ME/CFS, as well as patients diagnosed with fibromyalgia, MS, depression, heart disease, and psychosis. She continued to use antibiotics to successfully treat thousands of patients with underlying rickettsial infections, all of whom had been previously diagnosed with other ailments (predominantly ME/CFS, fibromyalgia, MS, and rheumatoid arthritis).
Dr. Jadin considers rickettsial infection to be an occult disease. That is, it remains dormant until another pathogen challenges the system. (This relates to Dr. Bell’s 1-2 punch theory.) At that point, the patient becomes symptomatic. This is a compelling theory for the origin of ME/CFS, as it adequately explains the wide variety of triggers as well as the multiplicity of symptoms. Significantly, another tick-borne rickettsial bacterium, borrelia, has been found in patients diagnosed with ME/CFS. Several species of borrelia are known to cause Lyme disease, which produces central nervous system, joint, and cardiovascular symptoms, as well as fatigue.
There are about 1.5 million different types of fungi, with many more yet to be identified. Unfortunately, while most of these species are benign, a few emit toxic substances, known as volatile organic compounds (VOCs). When certain species of molds proliferate indoors in damp environments, as occurs in “sick building syndrome,” they can exceed the body’s ability to handle the toxins.
People who are chronically exposed to VOCs can experience fatigue, weakness, GERD, aching, unusual stabbing pains all over, light sensitivity, transient blurred vision, shortness of breath, cough, numbness, tingling, confusion, constipation and diarrhea, morning stiffness, a metallic taste in the mouth, diarrhea at night, thirst, frequent urination, static shocks, and hypothalamic problems such as mood swings, appetite swings, sweats, and trouble controlling body temperature. Mold has a number of strong negative effects on the body, including the creation of oxidative stress, a decrease in reduced glutathione, perforations in the blood-brain barrier, and destruction of intestinal cells.
At the 2004 American Association of Chronic Fatigue Syndrome conference, Dr. Shoemaker presented 89 patients “desperately ill” with ME/CFS. Of these patients, 79 possessed mold susceptible genotypes. He noted a number of other immune system commonalities between people with mold exposure illnesses and ME/CFS. In both sets of patients, alpha interferon is increased. RNase L, the enzyme that is elevated in ME/CFS patients, is also elevated after exposure to mold.
A 2003 review of mycotoxin exposure-related health risks conducted by Anyanwu et al. found that depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations through mycotoxin-induced natural killer cell activity. The authors concluded that “chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures.”
Moreover, Anyanwu et al. observed in a later paper that patients with chronic mold exposure show vitamin B12 deficiencies, resulting in a disruption in the methylation cycle. The authors proposed that it is the interruption of B12 function that leads to the neurological symptoms of mold exposure. A 2013 study headed by Joseph Brewer found that mycotoxins were present in the urine of 93% of ME/CFS patients examined (104 out of 112). None were found in healthy controls.
Environmental toxins have frequently been implicated as possible causes of ME/CFS, particularly in patients with gradual onset. Dr. Majid Ali, a physician who believes that ME/CFS is caused by toxic overload, writes in his book, The Canary and Chronic Fatigue, that “chronic fatigue sufferers are human canaries-unique people who tolerate poorly the biologic stressors of the late 20th century.”
Dr. Martin Pall has noted that the symptoms of post-radiation syndrome are identical to those of ME/CFS. Alan Cocchetto, Medical Director of the National CFIDS Foundation, has identified some unique mitochondrial characteristics in his research that implicate low level radiation as the catalyst for some patients. As Dr. Pall’s NO/ONOO- model can also lead to mitochondrial defects, the two models may eventually prove to be similar, if not the same.
Pesticides are the primary focus of researchers investigating environmental causes of ME/CFS. A retrospective study conducted in Scotland, found that sheep farmers who had been exposed to organophosphates in sheep dips showed high prevalence of chronic fatigue and that higher chronic fatigue scores were associated with higher exposure to organophosphate pesticides.
Dunstan and colleagues found that serum levels of organochlorine (a chemical found in pesticides) was higher in ME/CFS than in controls. There were no significant differences in organochlorine levels between those ME/CFS patients with a history of toxic chemical exposure, and those without. The researchers concluded that the exclusion of patients from the CDC definition of ME/CFS on the basis of a history of exposure to toxic chemicals was not valid, and that low level organochlorine bioaccumulation might lead to the development of ME/CFS.
A third group of Scottish researchers led by Dr. Faisel Khan, found a link between ME/CFS, Gulf War Illness (GWI) and agricultural workers exposed to organophosphate pesticides. All three exhibited cholinergic abnormalities, however only the ME/CFS group showed abnormalities in the vascular system. They concluded that ME/CFS had a different etiology from either GWI or pesticide exposure.
Two later studies by the authors found that sensitivity to acetylcholine was restricted to those patients who fit descriptions for ME and post-viral fatigue syndromes, but not those for Gulf War Illness or for those exposed to organophosphate compounds, or those with fibromyalgia. (For recent developments see: Gulf War Illness: New Report Lauds Treatment Research, Confirms Toxic Causes.)
The authors were confident that the finding of increased sensitivity to acetylcholine in ME/CFS patients was “robust and unusual,” but did not conclude that pesticide exposure was causal.
ME/CFS does not fall into the category of a genetic disease, for even though it can occur in family groups, it also occurs in groups whose only risk factor was being in the same place at the same time (e.g., the Royal Free outbreak). Families who contract the flu simultaneously certainly cannot be said to have a genetic disease. However, genes can still play a prominent role in determining who gets sick, and for how long. Clearly, some people are better at resisting infection than others. The reason for this may lie not only in the efficiency of their immune systems, but in their genes.
The strongest evidence for genetic involvement comes from twins who develop the same illness, but have been separated at birth (e.g., adoption). Because the social and physical environments are different, it is assumed that genetic traits play a large contributory role.
Sabath et al. conducted a twin study in 2002 that revealed immune system abnormalities in discordant twins (one twin had ME/CFS, the other didn’t). Significant reductions in T cell subtypes, including the expression of NK cells and total lymphocytes, were noted in ME/CFS twins. This confirms immunological findings in the general ME/CFS population.
In 2004, a study performed by Mahurin et al. showed that discordant twins had much slower reaction times on all speed-related cognitive tests than healthy twins. The researchers suggested that their findings indicated a central information processing deficit in the brain. A subsequent study conducted by Claypoole et al. found that among discordant twins, those with ME/CFS exhibited decreases in motor functions, speed of information processing, verbal memory, and executive functioning. Interestingly, the twins with sudden onset demonstrated slower information processing compared with those with a gradual onset of the illness.
Non-twin genetic studies have found that the expression of genes linked to a number of ME/CFS symptoms differs sharply from those who are healthy. Changes in gene expression of lymphocytes, indicating subtle changes in the immune system, were documented in ME/CFS patients by Powell et al. And in 2007, a group of Swedish researchers led by Hanna Gräns found significantly lower messenger RNA expression levels of estrogen receptors in female patients compared with healthy controls. The researchers stated that their finding was consistent with an “immune-mediated pathogenesis” of ME/CFS.
In 2005 Whistler et al. located a set of exercise-responsive genes that differed between patients and controls, adding a genetic component to the hallmark symptom of ME/CFS: exercise intolerance. Significantly, greater numbers of genes involved in ion transport and ion channel activity (two molecular functions involved in physical activity) were exaggerated after exercise in ME/CFS patients.
Also in 2005, Kaushik et al. at the Imperial College in London, found 35 genes in ME/CFS patients which were different from controls. This abnormal gene expression could account for many ME/CFS symptoms, including fatigue, exercise intolerance, cognitive deficits, and cardiovascular problems. The authors concluded that this profile “indicated T cell activation and perturbation of neuronal and mitochondrial function.” These findings would support immune and cellular dysfunctions consistent with a viral etiology.
More recently, a group of 17 researchers in Great Britain confirmed a differential expression for 88 genes; 85 were upregulated, and 3 were down regulated in 55 ME/CFS patients. According to the researchers, the most highly represented functions were “hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection.”
Twelve of the genes associated with EBV infection were upregulated, underscoring the importance of EBV in ME/CFS. Another significant finding, especially in light of the recent studies documenting reduced white matter in the brains of people with ME/CFS, was a gene mutation associated with vanishing white matter disease.
Recent research by Alan and Kathleen Light has found that certain genes react to physical exertion in different ways for people with chronic fatigue syndrome or fibromyalgia. They are currently examining the role genes play in exercise intolerance. (See: Sufferers of chronic fatigue, fibromyalgia have hope in new diagnostic tool)
Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE. “Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients.” J Clin Virol. 2000 May;16(3):179-91. (Abstract)
Anyanwu E, Campbell AW, Jones J, Ehiri JE, Akpan AI. “The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.” Scientific World Journal. 2003 Nov 13;3:1128-37.
Anyanwu EC, Morad M, Campbell AW. “Metabolism of mycotoxins, intracellular functions of vitamin B12, and neurological manifestations in patients with chronic toxigenic mold exposures. A review.” Scientific World Journal, 2004 Aug 26;4:736-45.
Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. “Chronic fatigue syndrome, the immune system and viral infection.” Brain Behav Immun. 2012 Jan;26(1):24-31.
Brewer, Joseph H., Jack D. Thrasher, David C. Straus, Roberta A. Madison, and Dennis Hooper. “Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome.” Toxins 2013, 5(4), 605-617.
Cacioppo JT, Kiecolt-Glaser JK, Malarkey WB, Laskowski BF, Rozlog LA, Poehlmann KM, Burleson MH, Glaser R. “Autonomic and glucocorticoid associations with the steady-state expression of latent Epstein-Barr virus.” Horm Behav. 2002 Aug;42(1):32-41.
Campbell, Andrew W., Jack D, Thrasher, Michael Gray, and Aristo Vojdani. “Mold and Mycotoxins: Effects on the Neurological and Immune Systems in Humans.” Advances in Applied Microbiology, 2004;55:375-406.
Chapenko S, Krumina A, Kozireva S, et al. “Activation of human herpesvirus 6 and 7 in patients with chronic fatigue syndrome.” J Clin Virol 2006, 37(Suppl 1):S47-51.
Chen T, Hudnall SD. “Anatomical mapping of human herpesvirus reservoirs of infection.” Mod Pathol. 2006 May;19(5):726-37.
Chia J, Chia A, Voeller M, Lee T, Chang R. “Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence.” J Clin Pathol. 2010 Feb;63(2):165-8. PMID: 1982890
Chia, John K S, Andrew Y Chia. “Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach.” J Clin Pathol 2007;0:1-6.
Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. “A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset.” Neuropsychology. 2007 Jul;21(4):507-13.
Corrigan FM, MacDonald S, Brown A, Armstrong K, Armstrong EM. “Neurasthenic fatigue, chemical sensitivity and GABAa receptor toxins.” Med Hypotheses. 1994 Oct;43(4):195-200.
De Meirleir K, Bisbal C, Campine I, De Becker P, Salehzada T, Demettre E, Lebleu B. “A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome.” Am J Med. 2000 Feb;108(2):99-105.
Dunstan, R. Hugh, Mark Donohoe,Warren Taylor, Timothy K. Roberts, Raymond N. Murdoch, Jennifer A. Watkins, Neil R. McGregor. “A Preliminary Investigation Of Chlorinated Hydrocarbons And Chronic Fatigue Syndrome.” Med J. Australia 1995 163:294-297.
Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T,Herberman R, Kiecolt-Glaser J, Williams MV. “Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer.” Brain Behav Immun. 2005 Mar;19(2):91-103.
Glaser, Ronald, PhD, and Janice K. Kiecolt-Glaser, PhD. “Stress-Associated Immune Modulation: Relevance to Viral Infections and Chronic Fatigue Syndrome.” Am J Med. 1998;105(3A): 35S- 42S.
Gräns, Hanna, Maria Nilsson, Karin Dahlman-Wright, Birgitta Evengård. “Reduced levels of oestrogen receptor ? mRNA in Swedish patients with chronic fatigue syndrome.” J Clin Pathol 2007;60:195-198
Gustaw K. [Chronic fatigue syndrome following tick-borne diseases]. Neurol Neurochir Pol. 2003 Nov-Dec;37(6):1211-21.
Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A. “Post-infective and chronic fatigue syndromes precipitated by viral pathogens: prospective cohort study.” BMJ 2006, 333:57.
Jadin, CL, MD. “The Rickettsial Approach and treatment of patients presenting with CFS, Fibromyalgia, Rheumatoid Arthritis and Neurological Dysfunction.” Manly Conference, South Africa, February 1999.
Kaushik, N, D Fear, S C M Richards, C R McDermott, E F Nuwaysir, P Kella, T J Harrison, R J Wilkinson, D A J Tyrrell, S T Holgate, J R Kerr. “Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.” J Clin Pathol. 2005;58:826-832.
Khan F, Kennedy G, Spence VA, Newton DJ, Belch JJ. “Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure.” Clin Sci (Lond). 2004 Feb;106(2):183-9.
Kennedy PG. “Varicella-zoster virus latency in human ganglia.” Rev Med Virol. 2002 Sep-Oct;12(5):327-34.
Kennedy G, Spence V, Underwood C, Belch JJ. “Increased neutrophil apoptosis in chronic fatigue syndrome.” J Clin Pathol. 2004 Aug;57(8):891-3.
Kerr, J.R. “Pathogenesis of Parvovirus B19 Infection: Host Gene Variability, and Possible Means and Effects of Virus Persistence.” J. Vet. Med. B 52, 335-339 (2005)
Jonathan R. Kerr, Robert Petty, Beverley Burke, John Gough, David Fear, Lindsey I. Sinclair, Derek L. Mattey, Selwyn C. M. Richards, Jane Montgomery, Don A. Baldwin, Paul Kellam, Tim J Harrison, George E. Griffin, Janice Main, Derek Enlander, David J. Nutt, Stephen T. Holgate. “Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.” J Infect Dis. (2008) 197 (8): 1171-1184.
Komaroff, AL. “Is human herpesvirus-6 a trigger for chronic fatigue syndrome?” J Clin Virol. 2006 Dec;37 Suppl 1:S39-46.
Lerner, Martin A and Safedin Beqaj. “A paradigm linking herpesvirus immediate-early gene expression apoptosis and myalgic encephalomyelitis chronic fatigue syndrome.” Dovepress. February 2011 Volume 2011:3 Pages 19 – 24.
Lerner, Martin A., Safedin H Beqaj, Ken Gill, James Edington, James T Fitzgerald, Robert G Deeter. “An update on the management of glandular fever (infectious mononucleosis) and its sequelae caused by Epstein-Barr virus (HHV-4): new and emerging treatment strategies.” Virus Adaptation and Treatment, 23 Sept 2010.
Mahurin RK, Claypoole KH, Goldberg JH, Arguelles L, Ashton S, Buchwald D. “Cognitive processing in monozygotic twins discordant for chronic fatigue syndrome.” Neuropsychology, 2004 Apr;18(2):232-9.
Martin, W. John. “Severe Stealth Virus Encephalopathy Following Chronic Fatigue Syndrome-Like Illness: Clinical and Histopathological Features.” Pathobiology, S. Karger AG, 1996, Vol. 64, 1-8
Nasralla M, Haier J, Nicolson GL. “Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome.” Eur J Clin Microbiol Infect Dis. 1999 Dec;18(12):859-65.
Nicolson GL, Gan R, Haier J. “Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms.” APMIS. 2003 May;111(5):557-66.
Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K. “High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients.” FEMS Immunol Med Microbiol. 2002 Nov 15;34(3):209-14.
Pall ML. “Post-radiation syndrome as a NO/ONOO? – cycle, chronic fatigue syndrome-like disease.” Med Hypotheses. 2008 Oct;71(4):537-41. (Abstract)
Powell R, Ren J, Lewith G, Barclay W, Holgate S, Almond J. “Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients.” Clin Exp Allergy. 2003 Oct;33(10):1450-6.
Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigallo E. “Chronic fatigue syndrome following a toxic exposure.” Sci Total Environ. 2001 Apr 10;270(1-3):27-31.
Sabath DE, Barcy S, Koelle DM, Zeh J, Ashton S, Buchwald D. “Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome.” J Infect Dis. 2002 Mar 15;185(6):828-32.
Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. “Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome.” Intervirology. 1995;38(5):269-73.
Shapiro, JS. “Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?” Med Hypotheses. 2009 Nov;73(5):728-34.
Spence,V.A., F. Khan, G. Kennedy, N.C. Abbot, J.J.F. Belch. “Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome.” Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 403-407
Tahmaz N, Soutar A, Cherrie JW. “Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a U.K. pharmacovigilance scheme.” Ann Occup Hyg. 2003 Jun;47(4):261-7.
Vojdani, Aristo and Charles W. Lapp. “The Relationship Between Chronic Fatigue Syndrome and Chemical Exposure.” Journal of Chronic Fatigue Syndrome. Volume 5, Number 3 / 4, 1999.
Vernon, Suzanne D, Toni Whistler, Barbara Cameron, Ian B Hickie. William C Reeves and Andrew Lloyd. “Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus.” BMC Infectious Diseases 2006, 6:15
Whistler, Toni, James F Jones, Elizabeth R Unger, and Suzanne D Vernon. “Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects.” BMC Physiol. 2005; 5: 5.
Yang, Eric V.; Jeanette I. Webster Marketon, Min Chen, Kwok Wai Lo, Seung-jae Kim, and Ronald Glaser. “Glucocorticoids activate Epstein Barr Virus lytic replication through the upregulation of immediate early BZLF1 gene expression.” Brain Behav Immun. 2010; 24: 1089-1096.