Category: Pathogenesis

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

Abstract:

Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms.

More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

 

Source: Morris G, Berk M, Walder K, Maes M. The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability. Mol Neurobiol. 2016 May;53(4):2550-71. doi: 10.1007/s12035-015-9262-7. Epub 2015 Jun 17. https://www.ncbi.nlm.nih.gov/pubmed/26081141

 

Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women

Abstract:

OBJECTIVE: This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS).

METHODS: This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls.

RESULTS: Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset.

CONCLUSIONS: Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.

 

Source: Boneva RS, Lin JM, Unger ER. Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women. Menopause. 2015 Aug;22(8):826-34. doi: 10.1097/GME.0000000000000411. https://www.ncbi.nlm.nih.gov/pubmed/25647777

 

Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies

Abstract:

BACKGROUND: Fibromyalgia often coexists and overlaps with other syndromes such as chronic fatigue, irritable bowel syndrome, and interstitial cystitis. Chronic stress has been implicated in the pathogenesis of these illnesses. The sympathetic nervous system is a key element of the stress response system. Sympathetic dysfunction has been reported in these syndromes, raising the possibility that such dysautonomia could be their common clustering underlying pathogenesis.

OBJECTIVE: The objective of this study was to carry out a review of all published comparative case-control studies investigating sympathetic nervous system performance in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis.

METHODS: Online databases PubMed and EMBASE were accessed using the following key words: autonomic (OR) sympathetic (AND) fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. All entries up to December 10th 2012 were reviewed by 2 independent investigators searching for case-control studies in humans. The Method for Evaluating Research and Guidelines Evidence adapted to the Scottish Intercollegiate Guidelines Network was used to rank the level of evidence contained in the selected articles.

RESULTS: A total of 196 articles are included in this review. The most often used methods to assess sympathetic functionality were heart rate variability analysis, sympathetic skin response, tilt table testing, and genetic studies. The majority of studies (65%) described sympathetic nervous system predominance in these overlapping syndromes. In contrast, 7% of the studies found parasympathetic predominance.

CONCLUSIONS: This review demonstrates that sympathetic nervous system predominance is common in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. This concordance raises the possibility that sympathetic dysfunction could be their common underlying pathogenesis that brings on overlapping clinical features. The recognition of sympathetic predominance in these 4 syndromes may have potential clinical implications. It may be worth exploring the use of nonpharmacological measures as well as drug therapies aimed to regain autonomic balance.

 

Source: Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014 Apr;20(3):146-50. doi: 10.1097/RHU.0000000000000089. https://www.ncbi.nlm.nih.gov/pubmed/24662556

 

A metagenomic approach to investigate the microbial causes of myalgic encephalomyelitis/chronic fatigue syndrome: moving beyond XMRV

Three years ago, a novel association between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the murine retrovirus XMRV was published.[1] Since then, 191 papers have been published on the subject (NCBI PubMed, accessed 6 November 2012), largely disproving the initial association, a trend confirmed by a recent multicentre blinded trial which definitively concluded that there is no association between ME/CFS and XMRV.[2] It is therefore time to revisit the investigation of ME/CFS aetiology. Metagenomics offers a promising new opportunity for hypothesis discovery in microbial associations with ME/CFS, and we describe herein the technical basis of this approach and its advantages in aetiological agent investigation.

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835061/

 

Source: Miller RR, Gardy JL, Tang P, Patrick DM. A metagenomic approach to investigate the microbial causes of myalgic encephalomyelitis/chronic fatigue syndrome: moving beyond XMRV. Fatigue. 2013 Oct;1(4):185-189. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835061/ (Full article)

 

A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a severe, systemic illness characterized by persistent, debilitating and medically unexplained fatigue. The etiology and pathophysiology of CFS remains obscure, and diagnosis is formulated through the patient’s history and exclusion of other medical causes. Thereby, the availability of biomarkers for CFS could be useful for clinical research. In the present study, we used a proteomic approach to evaluate the global changes in the salivary profile in a couple of monozygotic twins who were discordant for CFS. The aim was to evaluate differences of salivary protein expression in the CFS patient in respect to his healthy twin.

METHODS: Saliva samples were submitted to two-dimensional electrophoresis (2DE). The gels were stained with Sypro, and a comparison between CFS subject and the healthy one was performed by the software Progenesis Same Spot including the Analysis of variance (ANOVA test). The proteins spot found with a ≥2-fold spot quantity change and p<0.05 were identified by Nano-liquid chromatography electrospray ionization tandem mass spectrometry. To validate the expression changes found with 2DE of 5 proteins (14-3-3 protein zeta/delta, cyclophilin A, Cystatin-C, Protein S100-A7, and zinc-alpha-2-glycoprotein), we used the western blot analysis. Moreover, proteins differentially expressed were functionally analyzed using the Ingenuity Pathways Analysis software with the aim to determine the predominant canonical pathways and the interaction network involved.

RESULTS: The analysis of the protein profiles allowed us to find 13 proteins with a different expression in CFS in respect to control. Nine spots were up-regulated in CFS and 4 down-regulated. These proteins belong to different functional classes, such as inflammatory response, immune system and metabolism. In particular, as shown by the pathway analysis, the network built with our proteins highlights the involvement of inflammatory response in CFS pathogenesis.

CONCLUSIONS: This study shows the presence of differentially expressed proteins in the saliva of the couple of monozygotic twins discordant for CFS, probably related to the disease. Consequently, we believe the proteomic approach could be useful both to define a panel of potential diagnostic biomarkers and to shed new light on the comprehension of the pathogenetic pathways of CFS.

 

Source: Ciregia F, Giusti L, Da Valle Y, Donadio E, Consensi A, Giacomelli C, Sernissi F, Scarpellini P, Maggi F, Lucacchini A, Bazzichi L. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2;11:243. doi: 10.1186/1479-5876-11-243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850462/ (Full article)

 

Neuromuscular strain as a contributor to cognitive and other symptoms in chronic fatigue syndrome: hypothesis and conceptual model

Abstract:

Individuals with chronic fatigue syndrome (CFS) have heightened sensitivity and increased symptoms following various physiologic challenges, such as orthostatic stress, physical exercise, and cognitive challenges. Similar heightened sensitivity to the same stressors in fibromyalgia (FM) has led investigators to propose that these findings reflect a state of central sensitivity.

A large body of evidence supports the concept of central sensitivity in FM. A more modest literature provides partial support for this model in CFS, particularly with regard to pain. Nonetheless, fatigue and cognitive dysfunction have not been explained by the central sensitivity data thus far.

Peripheral factors have attracted attention recently as contributors to central sensitivity. Work by Brieg, Sunderland, and others has emphasized the ability of the nervous system to undergo accommodative changes in length in response to the range of limb and trunk movements carried out during daily activity. If that ability to elongate is impaired-due to movement restrictions in tissues adjacent to nerves, or due to swelling or adhesions within the nerve itself-the result is an increase in mechanical tension within the nerve. This adverse neural tension, also termed neurodynamic dysfunction, is thought to contribute to pain and other symptoms through a variety of mechanisms. These include mechanical sensitization and altered nociceptive signaling, altered proprioception, adverse patterns of muscle recruitment and force of muscle contraction, reduced intra-neural blood flow, and release of inflammatory neuropeptides. Because it is not possible to differentiate completely between adverse neural tension and strain in muscles, fascia, and other soft tissues, we use the more general term “neuromuscular strain.”

In our clinical work, we have found that neuromuscular restrictions are common in CFS, and that many symptoms of CFS can be reproduced by selectively adding neuromuscular strain during the examination. In this paper we submit that neuromuscular strain is a previously unappreciated peripheral source of sensitizing input to the nervous system, and that it contributes to the pathogenesis of CFS symptoms, including cognitive dysfunction.

 

Source: Rowe PC, Fontaine KR, Violand RL. Neuromuscular strain as a contributor to cognitive and other symptoms in chronic fatigue syndrome: hypothesis and conceptual model. Front Physiol. 2013 May 16;4:115. doi: 10.3389/fphys.2013.00115. eCollection 2013.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655286/ (Full article)

 

Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course

Abstract:

BACKGROUND: A high prevalence of chronic fatigue has previously been reported following giardiasis after a large waterborne outbreak in Bergen, Norway in 2004. The aim of this study was to describe and evaluate differential diagnoses and natural course of fatigue five years after giardiasis among patients who reported chronic fatigue three years after the infection.

METHODS: Patients who three years after Giardia infection met Chalder’s criteria for chronic fatigue (n=347) in a questionnaire study among all patients who had laboratory confirmed giardiasis during the Bergen outbreak (n=1252) were invited to participate in this study five years after the infection (n=253). Structured interviews and clinical examination were performed by specialists in psychiatry, neurology and internal medicine/infectious diseases. Fukuda et al’s 1994 criteria were used to diagnose chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). Self-reported fatigue recorded with Chalder Fatigue Questionnaire three and five years after infection were compared.

RESULTS: 53 patients were included. CFS was diagnosed in 41.5% (22/53) and ICF in 13.2% (7/53). Chronic fatigue caused by other aetiology was diagnosed in 24.5% (13/53); five of these patients had sleep apnoea/hypopnoea syndrome, six had depression and five anxiety disorder, and among these two had more than one diagnosis. Fatigue had resolved in 20.8% (11/53). Self-reported fatigue score in the cohort was significantly reduced at five years compared to three years (p<0.001).

CONCLUSION: The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study. Improvement of chronic fatigue in the period from three to five years after giardiasis was found.

 

Source: Mørch K, Hanevik K, Rivenes AC, Bødtker JE, Næss H, Stubhaug B, Wensaas KA, Rortveit G, Eide GE, Hausken T, Langeland N. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterol. 2013 Feb 12;13:28. doi: 10.1186/1471-230X-13-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598369/ (Full article)

 

A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Abstract:

Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

 

Source: Blankfield A. A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Int J Tryptophan Res. 2012;5:27-32. doi: 10.4137/IJTR.S10085. Epub 2012 Sep 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460668/ (Full article)

 

Loss of stress response as a consequence of viral infection: implications for disease and therapy

Abstract:

Herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. Having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. Host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. In the case of Newcastle disease virus, the effects of viral infection on heat shock proteins may be leveraged as a therapy for cancer. Finally, the search for a specific virus being responsible for a condition like chronic fatigue syndrome may not be worthwhile if the disease is simply a nonspecific response to viral infection.

 

Source: Hooper PL, Hightower LE, Hooper PL. Loss of stress response as a consequence of viral infection: implications for disease and therapy. Cell Stress Chaperones. 2012 Nov;17(6):647-55. doi: 10.1007/s12192-012-0352-4. Epub 2012 Jul 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468676/ (Full article)

 

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS.

Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients.

In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients.

If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients’ symptom profiles.

Copyright © 2012 Elsevier Ltd. All rights reserved.

 

Source: Pacini S, Fiore MG, Magherini S, Morucci G, Branca JJ, Gulisano M, Ruggiero M. Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Med Hypotheses. 2012 Sep;79(3):403-7. doi: 10.1016/j.mehy.2012.06.007. Epub 2012 Jul 12. https://www.ncbi.nlm.nih.gov/pubmed/22795611