A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications

Abstract:

Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome(CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.

Source: Monro JA, Puri BK. A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. Mol Neurobiol. 2018 Feb 6. doi: 10.1007/s12035-018-0928-9. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29411266

Impact of Rantes from jawbone on Chronic Fatigue Syndrome

Abstract:

This study elucidates the question of whether chronic inflammation in the jawbone contributes to the development of Chronic Fatigue Syndrome (CFS). Fatty degenerative osteonecrosis in jawbone (FDOJ) may contribute to CFS by induction of inflammatory mediators.

We examined seven cytokines by multiplex analysis in jawbone samples from two groups of patients. In order to clarify neurological interrelations, specimens from 21 CFS patients were analyzed from areas of previous surgery in the retromolar wisdom tooth area. Each of the retromolar jawbone samples showed clinically fatty degenerated and osteonecrotic medullary changes. As control, healthy jawbone specimens from 19 healthy patients were analyzed. All fatty necrotic and osteolytic jawbone (FDOJ) samples showed high expression of RANTES and fibroblast growth factor (FGF)-2. FDOJ cohorts showed a 30-fold mean overexpression of RANTES and a 20-fold overexpressed level of FGF-2 when compared to healthy controls. As RANTES is discussed in the literature as a possible contributor to inflammatory diseases, we hypothesize that FDOJ in areas of improper and incomplete wound healing in the jawbone may hyperactivate signaling pathways.

Constituting a hidden source of “silent inflammation” FDOJ may represent a hitherto unknown cause for the development of CFS.

Source: Lechner J, Huesker K, Von Baehr V. Impact of Rantes from jawbone on Chronic Fatigue Syndrome. J Biol Regul Homeost Agents. 2017 Apr-Jun;31(2):321-327. https://www.ncbi.nlm.nih.gov/pubmed/28685531

HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway

Abstract:

Background: Vaccination has been suggested to be involved in the aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). HPV vaccine was introduced in the Norwegian Childhood Immunisation Programme and offered 12 year old girls from 2009. We studied the association between HPV vaccination and risk of CFS/ME and also assessed medical history in relation to both risk of CFS/ME and HPV vaccine uptake.

Methods: Individual data from national registries, including the Norwegian Population Registry, the Norwegian Patient Registry and the Norwegian Immunisation Registry were linked using the unique personal identification number. Yearly incidence rates of CFS/ME for 2009–2014 were calculated among the 824,133 boys and girls, aged 10–17 living in Norway during these 6 years. A total of 176,453 girls born 1997–2002 were eligible for HPV vaccination and included in further analyses. Hazard ratios (HRs) of CFS/ME were estimated using Cox regression. Risk differences (RDs) of vaccine uptake were estimated with binomial regression.

Results: A similar yearly increase in incidence rate of CFS/ME was observed among girls and boys, IRR = 1.15 (95% confidence interval (CI) 1.10–1.19) and 1.15 (95% CI 1.09–1.22), respectively. HPV vaccination was not associated with CFS/ME, HR = 0.86 (95% CI 0.69–1.08) for the entire follow-up period and 0.96 (95% CI 0.64–1.43) for the first two years after vaccination. The risk of CFS/ME increased with increasing number of previous hospital contacts, HR = 5.23 (95% CI 3.66–7.49) for 7 or more contacts as compared to no contacts. Girls with 7 or more hospital contacts were less likely to be vaccinated than girls with no previous hospital contacts, RD = −5.5% (95% CI −6.7% to −4.2%).

Conclusions: No indication of increased risk of CFS/ME following HPV vaccination was observed among girls in the first 6 birth cohorts offered HPV vaccine through the national immunisation programme in Norway.

Source: Berit Feiring, Ida Laake, Inger Johanne Bakken, Margrethe Greve-Isdahl, Vegard Bruun Wyller, Siri E. Haberg, Per Magnus, Lill Trogstad. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine, June 23, 2017. http://www.sciencedirect.com/science/article/pii/S0264410X17308083

Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review

Abstract:

BACKGROUND: The pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of D-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of D-lactic acidosis (D-la).

METHODS: D-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high D-lactate levels. Fifty-nine D-la episodes were included in the qualitative synthesis comparing D-la symptoms with ME/CFS diagnostic criteria. A narrative review of D-la mechanisms and relevance for ME/CFS was provided.

RESULTS: The majority of neurological disturbances reported in D-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported D-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS.

LIMITATIONS: Interpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for D-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined.

CONCLUSIONS: Shared symptomatology and underlying microbiota-gut-brain interactions raise the possibility of a continuum of acute (D-la) versus chronic (ME/CFS) presentations related to D-lactate absorption. Measurement of D-lactate in ME/CFS is needed to effectively evaluate whether subclinical D-lactate levels affect neurological symptoms in this clinical population.

Source: Wallis A, Ball M, McKechnie S, Butt H, Lewis DP, Bruck D. Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review. J Transl Med. 2017 Jun 7;15(1):129. doi: 10.1186/s12967-017-1229-1. https://www.ncbi.nlm.nih.gov/pubmed/28592308

XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable

Abstract:

A few years ago, a highly significant association between the xenotropic murine leukemia virus-related virus (XMRV) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex debilitating disease of poorly understood etiology and no definite treatment, was reported in Science, raising concern for public welfare. Successively, the failure to reproduce these findings, and the suspect that the diagnostic PCR was vitiated by laboratory contaminations, led to the retraction of the paper.

Notwithstanding, XMRV continued to be the subject of researches and public debates. Occasional positivity in humans was also detected recently, even if the data always appeared elusive and non-reproducible. In this study, we discuss the current status of this controversial association and propose that a major role in the unreliability of the results was played by the XMRV genomic composition in itself. In this regard, we present bioinformatic analyses that show: (i) aspecific, spurious annealings of the available primers in multiple homologous sites of the human genome; (ii) strict homologies between whole XMRV genome and interspersed repetitive elements widespread in mammalian genomes. 'To further detail this scenario, we screen several human and mammalian samples by using both published and newly designed primers.

The experimental data confirm that available primers are far from being selective and specific. In conclusion, the occurrence of highly conserved, repeated DNA sequences in the XMRV genome deeply undermines the reliability of diagnostic PCRs by leading to artifactual and spurious amplifications. Together with all the other evidences, this makes the association between the XMRV retrovirus and CFS totally unreliable.

Source: Panelli S, Lorusso L, Balestrieri A, Lupo G, Capelli E. XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable. Front Public Health. 2017 May 22;5:108. doi: 10.3389/fpubh.2017.00108. ECollection 2017. http://journal.frontiersin.org/article/10.3389/fpubh.2017.00108/full (Full article)

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown etiology, classified as a neurological disorder by the World Health Organization (WHO). The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation. This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective. It is intended to provide stakeholders with a concise, integrated outline disease model in order to help demystify this major public health problem. The primary etiopathological factors presented are:

(A) Postural/biomechanical pain signaling, affecting adverse neuroexcitation, in the context of compression, constriction, strain, or damage of vertebral-regional bone and neuromuscular tissues;

(B) Immune mediated inflammatory sequelae, in the context of prolonged immunotropic neurotrophic infection-with lymphotropic/gliotropic/glio-toxic varieties implicated in particular;

(C) A combination of factors A and B. Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity. These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.

 

Source: Glassford JA. The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Physiol. 2017 Feb 17;8:88. doi: 10.3389/fphys.2017.00088. eCollection 2017. http://journal.frontiersin.org/article/10.3389/fphys.2017.00088/full (Full article)

 

Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?

Irritable bowel syndrome, chronic fatigue syndrome and anorexia nervosa may all have a common origin according to researchers.

They speculate that all three disorders may be caused by antibodies to the body’s own nerve cells because of a mistake by the immune system following infection.

At the moment, the ultimate cause of these illnesses remains a mystery.

Writing in Medical Hypotheses, Dr Jim Morris from the University Hospitals of Morecambe Bay NHS Trust, Dr Sue Broughton and Dr Quenton Wessels from Lancaster University say current explanations are unsatisfactory.

“Psychological factors might be important, but are unconvincing as the primary or major cause.

“There might, for instance, be an increased incidence of physical and sexual abuse in childhood in those who go on to manifest functional disorders. It is easy to see how this could influence symptoms in adults but it stretches credulity to imagine abuse as the sole and sufficient cause of the functional disorder.”

It is already well known that women are more at increased risk of autoimmune disease especially ones in which antibodies to the body’s own cells are thought to play a role, like thyroid disease, pernicious anemia and myasthenia gravis.

The researchers said: “The female to male ratio in these conditions is of the order of 10. The female excess in Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Anorexia Nervosa is equally extreme and therefore this fits with the idea that auto-antibodies to nerve cells could be part of the pathogenesis of these conditions.”

The formation of auto-antibodies is found mostly among women and increases with age, which could be why these disorders are more common in midlife. Even with anorexia, which reaches a peak at the age of 30, auto-antibodies have been found in the bodies of patients.

There are also links with infection in that the onset of IBS commonly follows an episode of infectious diarrhea while chronic fatigue syndrome can be triggered by infectious mononucleosis and viral hepatitis.

Even anorexia could be influenced by secretions from bacteria affecting the brain, triggering the production of antibodies which affect mood and motivation.

“Auto-antibodies acting on the (brain’s) limbic system could induce extremes of emotion including disgust and fear. These then become linked, in the minds of adolescent girls, to culturally determined ideas of what is, and what is not, the ideal body shape and size. It is then a small step for disgust and fear to be directed to food and obesity which the fashion industry currently demonizes.”

If their idea is proven, the researchers suggest that these disorders may be amenable to treatment using pooled immunoglobulin from the blood of healthy people, especially in severe cases of anorexia where life is threatened. It should also be possible to identify and eliminate from the gut the bacteria which are triggering auto-antibodies.

Journal Reference: J.A. Morris, S.J. Broughton, Q. Wessels. Microbes, molecular mimicry and molecules of mood and motivation. Medical Hypotheses, 2016; 87: 40 DOI:10.1016/j.mehy.2015.12.011

 

Source: Lancaster University. “Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?.” ScienceDaily. ScienceDaily, 25 April 2016. https://www.sciencedaily.com/releases/2016/04/160425100204.htm

 

Vaccine-Related Chronic Fatigue Syndrome In An Individual Demonstrating Aluminium Overload

A team of scientists have investigated a case of vaccine-associated chronic fatigue syndrome (CFS) and macrophagic myofasciitis in an individual demonstrating aluminium overload.

This is the first report linking aluminium overload with either of the two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in a patient.

The team, led by Dr Chris Exley, of the Birchall Centre at Keele University in Staffordshire, UK, has found a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events that are associated with autoimmune conditions, including chronic fatigue syndrome and macrophagic myofasciitis.

The CFS in a 43-year-old man, with no history of previous illness, followed a course of five vaccinations, each of which included an aluminium-based adjuvant. The latter are extremely effective immunogens in their own right and so improve the immune response to whichever antigen is administered in their presence. While the course of vaccinations was cited by an industrial injuries tribunal as the cause of the CFS in the individual, it was not likely to be a cause of the elevated body burden of aluminium. The latter was probably ongoing at the time when the vaccinations were administered and it is proposed that the cause of the CFS in this individual was a heightened immune response, initially to the aluminium in each of the adjuvants and thereafter spreading to other significant body stores of aluminium.

The result was a severe and ongoing immune response to elevated body stores of aluminium, which was initiated by a course of five aluminium adjuvant-based vaccinations within a short period of time. There are strong precedents for delayed hypersensitivity to aluminium in children receiving vaccinations which include aluminium-based adjuvants, with as many as 1% of recipients showing such a response.

While the use of aluminium-based adjuvants may be safe, it is also possible that for a significant number of individuals they may represent a significant health risk, such as was found in this case. With this in mind the ongoing programme of mass vaccination of young women in the UK against the human papilloma virus (HPV) with a vaccine which uses an aluminium based adjuvant may not be without similar risks.

Recent press coverage of myalgic encephalomyelitis (ME) or chronic fatigue syndrome has highlighted the potentially debilitating nature of this disease and related conditions. The cause of CFS is unknown.

 

Source: Keele University. (2008, November 18). Vaccine-Related Chronic Fatigue Syndrome In An Individual Demonstrating Aluminium Overload. ScienceDaily. Retrieved March 4, 2017 from  https://www.sciencedaily.com/releases/2008/11/081118141856.htm

 

Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome

Abstract:

BACKGROUND: The role of pathogen specific cellular immune responses against the eliciting pathogen in development of post-infectious chronic fatigue syndrome (PI-CFS) is not known and such studies are difficult to perform. The aim of this study was to evaluate specific anti-Giardia cellular immunity in cases that developed CFS after Giardia infection compared to cases that recovered well. Patients reporting chronic fatigue in a questionnaire study three years after a Giardia outbreak were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS and idiopathic chronic fatigue. Giardia specific immune responses were evaluated in 39 of these patients by proliferation assay, T cell activation and cytokine release analysis. 20 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls.

RESULTS: Patients were clinically classified into CFS (n = 15), idiopathic chronic fatigue (n = 5), fatigue from other causes (n = 9) and recovered from fatigue (n = 10). There were statistically significant antigen specific differences between these Giardia exposed groups and unexposed controls. However, we did not find differences between the Giardia exposed fatigue classification groups with regard to CD4 T cell activation, proliferation or cytokine levels in 6 days cultured PBMCs. Interestingly, sCD40L was increased in patients with PI-CFS and other persons with fatigue after Giardia infection compared to the non-fatigued group, and correlated well with fatigue levels at the time of sampling.

CONCLUSION: Our data show antigen specific cellular immune responses in the groups previously exposed to Giardia and increased sCD40L in fatigued patients.

 

Source: Hanevik K, Kristoffersen E, Mørch K, Rye KP, Sørnes S, Svärd S, Bruserud Ø, Langeland N. Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome. BMC Immunol. 2017 Jan 28;18(1):5. doi: 10.1186/s12865-017-0190-3.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279576/ (Full article)

 

Stressful Events in the Onset of Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a complex and multifactorial disease. Stressful situations experienced could be related to the presentation of the disease. Few studies have determined which factors could trigger CFS. The main objective of this study was to explore the stressful situations which can be associated with CFS presentation.

METHODS: Retrospective observational case-control study with CFS diagnosed patients according to the Fukuda’s criteria. Controls were matched to cases by sex, age and educational level with a 1:1 ratio. Participants aged between 18 and 75 years from the province of Lleida. Information was obtained through personal questionnaires. The measure of association was the odds ratio.

RESULTS: In total, 77 cases and 77 controls were included. Association found between stressful life events and presentation of disease were pregnancy ORa=31.7 (CI95%:2.2-456.7), spousal abuse ORa= 10.2 (CI95%:1.2-88.4) and mobbing ORa=6.9 (CI95%:1.3-36.9), eating disorders=7.5 (CI95%:1.3-42.1), car accident ORa=5.5 (CI95%:1.7-17 9), economic problems ORa=5.1 (CI95%:2.1-12.6) and changes in sleep habits ORa=2.8 (CI95%:1.1-7.5).

CONCLUSIONS: Stressful life events as pregnancy, spousal abuse, mobbing, eating disorders, car accident, economic problems and changes in sleep habits felt by those affected must be taken into consideration when compiling background information related to the onset of Chronic Fatigue Syndrome. Adequate identification of these stressful life events in risk people could contribute to early diagnosis of Chronic Fatigue Syndrome.

 

Source: Gimeno Pi I, Guitard Sein-Echaluce ML, Rosselló Aubach L, Torres Puig-Gros J, Fernández Solà J. Stressful Events in the Onset of Chronic Fatigue Syndrome. Rev Esp Salud Publica. 2016 Aug 18;90:e1-7. [Article in English, Spanish; Abstract available in Spanish from the publisher] https://www.ncbi.nlm.nih.gov/pubmed/27535808