Category: Pathophysiology

The aetiopathogenesis of fatigue: unpredictable, complex and persistent

Abstract:

BACKGROUND: Chronic fatigue syndrome is a common condition characterized by severe fatigue with post-exertional malaise, impaired cognitive ability, poor sleep quality, muscle pain, multi-joint pain, tender lymph nodes, sore throat or headache. Its defining symptom, fatigue is common to several diseases.

AREAS OF AGREEMENT: Research has established a broad picture of impairment across autonomic, endocrine and inflammatory systems though progress seems to have reached an impasse.

AREAS OF CONTROVERSY: The absence of a clear consensus view of the pathophysiology of fatigue suggests the need to switch from a focus on abnormalities in one system to an experimental and clinical approach which integrates findings across multiple systems and their constituent parts and to consider multiple environmental factors.

GROWING POINTS: We discuss this with reference to three key factors, non-determinism, non-reductionism and self-organization and suggest that an approach based on these principles may afford a coherent explanatory framework for much of the observed phenomena in fatigue and offers promising avenues for future research.

AREAS TIMELY FOR DEVELOPING RESEARCH: By adopting this approach, the field can examine issues regarding aetiopathogenesis and treatment, with relevance for future research and clinical practice.

© The Author 2016. Published by Oxford University Press.

 

Source: Clark JE, Fai Ng W, Watson S, Newton JL. The aetiopathogenesis of fatigue: unpredictable, complex and persistent. Br Med Bull. 2016 Mar;117(1):139-48. doi: 10.1093/bmb/ldv057. Epub 2016 Feb 12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782751/ (Full article)

 

Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study

Abstract:

Chronic Fatigue Syndrome (CFS) is a multisystem illness, which may be associated with imbalances in gut microbiota. This study builds on recent evidence that sleep may be influenced by gut microbiota, by assessing whether changes to microbiota in a clinical population known to have both poor sleep and high rates of colonization with gram-positive faecal Streptococcus, can improve sleep.

Twenty-one CFS participants completed a 22- day open label trial. Faecal microbiota analysis was performed at baseline and at the end of the trial. Participants were administered erythromycin 400 mg b.d. for 6 days. Actigraphy and questionnaires were used to monitor sleep, symptoms and mood. Changes in patients who showed a clinically significant change in faecal Streptococcus after treatment (responders; defined as post-therapy distribution<6%) were compared to participants who did not respond to treatment.

In the seven responders, there was a significant increase in actigraphic total sleep time (p=0.028) from baseline to follow up, compared with non-responders. Improved vigour scores were associated with a lower Streptococcus count (ρ=-0.90, p=0.037). For both the responders and the whole group, poorer mood was associated with higher Lactobacillus.

Short term antibiotic treatment appears to be insufficient to effect sustainable changes in the gut ecosystem in most CFS participants. Some improvement in objective sleep parameters and mood were found in participants with reduced levels of gram-positive gut microbiota after antibiotic treatment, which is encouraging. Further study of possible links between gut microorganisms and sleep and mood disturbances is warranted.

 

Source: Jackson ML, Butt H, Ball M, Lewis DP, Bruck D. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Sci. 2015 Nov;8(3):124-33. doi: 10.1016/j.slsci.2015.10.001. Epub 2015 Oct 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688574/ (Full article)

 

Support for the Microgenderome: Associations in a Human Clinical Population

Abstract:

The ‘microgenderome’ provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro-immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression.

Results revealed significant sex-specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota.

 

Source: Wallis A, Butt H, Ball M, Lewis DP, Bruck D. Support for the Microgenderome: Associations in a Human Clinical Population. Sci Rep. 2016 Jan 13;6:19171. doi: 10.1038/srep19171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725945/ (Full article)

 

The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders

Abstract:

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O&NS) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments.

In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O&NS, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist.

Other TRYCATs such as kynurenic acid function as antagonists of NMDA, α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine.

The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects.

Here we discuss the involvement of the above mentioned TRYCAT pathways in schizophrenia, Alzheimer’s disease and chronic fatigue syndrome.

Source: Morris G, Carvalho AF, Anderson G, Galecki P, Maes M. The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders. Curr Pharm Des. 2016;22(8):963-77. https://www.ncbi.nlm.nih.gov/pubmed/26667000

 

Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome

Abstract:

The ability to divide one’s attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging.

Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension.

In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively.

Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

 

Source: Mizuno K, Tanaka M, Tanabe HC, Joudoi T, Kawatani J, Shigihara Y, Tomoda A, Miike T, Imai-Matsumura K, Sadato N, Watanabe Y. Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome. Neuroimage Clin. 2015 Sep 10;9:355-68. doi: 10.1016/j.nicl.2015.09.001. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589845/ (Full article)

 

Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study

Abstract:

OBJECTIVE: The common concurrence of migraine and chronic fatigue syndrome (CFS) has been reported but whether migraine poses a higher risk of CFS remains unknown. In this retrospective case-control study, we examined the association between the 2 disorders by using a nationwide, population-based database in Taiwan.

METHODS: The data were retrieved and analyzed from the National Health Insurance Research Database (NHIRD) of Taiwan; 6902 newly diagnosed migraine cases from 2006-2010 were identified in a subset of the NHIRD, and 27,608 migraine-free individuals were randomly selected as the comparison cohort. The multivariate Cox proportional hazards regression model was used to investigate the risk of CFS in migraineurs after adjustment for demographic characteristics and comorbidities.

RESULTS: After adjustment for the covariates, the risk of CFS was 1.5-fold higher in the migraine cohort than in the comparison cohort (52.72 vs. 28.85 per 10,000 person-years). Intriguingly, the risk was most prominent in the oldest group (≥ 65 years), with a 2.11-fold increased risk (95% confidence interval 1.31-3.41) of CFS. In addition, the adjusted cumulative incidence of CFS in the follow-up years was higher in the migraine group (log-rank test, P < .0001), and CFS incidence appeared to increase with the frequency of migraine diagnoses.

CONCLUSION: The current study demonstrated an increased risk of CFS in migraineurs. Proposed mechanisms in previous studies such as mitochondrial dysfunction and central sensitization may underlie the shared pathophysiology of these seemingly distinct but potentially overlapping disorders.

Copyright © 2015 Elsevier Inc. All rights reserved.

 

Source: Lau CI, Lin CC, Chen WH, Wang HC, Kao CH. Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study. J Psychosom Res. 2015 Dec;79(6):514-8. doi: 10.1016/j.jpsychores.2015.10.005. Epub 2015 Oct 20. https://www.ncbi.nlm.nih.gov/pubmed/26505533

 

Timed loaded standing in female chronic fatigue syndrome compared with other populations

Erratum in

  • J Rehabil Res Dev. 2015;52(7):859.

Abstract:

Patients with chronic fatigue syndrome (CFS), like patients with osteoporosis, have similar difficulties in standing and sitting. The aim of the study was to compare combined trunk and arm endurance among women with CFS (n = 72), women with osteoporosis (n = 30), nondisabled women (n = 55), and women from non-industrialized countries (n = 58) using the timed loaded standing (TLS) test. TLS measures how long a person can hold a 1 kg dumbbell in each hand in front of him or her with straight arms. TLS was higher in the industrialized nondisabled population than in the non-industrialized study population (p < 0.001) and in patients with osteoporosis (p = 0.002).

TLS was lower in patients with CFS than in nondisabled controls (p < 0.001). After adjusting for age, body height, and weight, combined trunk and arm endurance was lower in CFS patients than in osteoporotic patients, even though the patients with osteoporosis were more than 25 yr older (p < 0.001) [corrected]. In CFS, TLS was lower than in the non-industrialized group (p = 0.02). Since only women were studied, external validity of the results is limited to adult female patients with CFS. TLS revealed a specific biomechanical weakness in CFS patients that can be taken into account from the onset of a rehabilitation program. We propose that influencing the quality, rather than the quantity, of movement could be used in the rehabilitation.

 

Source: Eyskens JB, Nijs J, D’Août K, Sand A, Wouters K, Moorkens G. Timed loaded standing in female chronic fatigue syndrome compared with other populations. J Rehabil Res Dev. 2015;52(1):21-9. doi: 10.1682/JRRD.2014.03.0086. http://www.rehab.research.va.gov/jour/2015/521/JRRD-2014-03-0086.html (Full article)

 

Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues

Abstract:

There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined.

Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM.

Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems’ abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.

© 2015 S. Karger AG, Basel.

 

Source: Romano GF, Tomassi S, Russell A, Mondelli V, Pariante CM. Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. Adv Psychosom Med. 2015;34:61-77. doi: 10.1159/000369085. Epub 2015 Mar 30. https://www.ncbi.nlm.nih.gov/pubmed/25832514

 

Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome

Abstract:

OBJECTIVES: There is evidence that inflammatory, oxidative and nitrosative stress (IO&NS) pathways participate in the pathophysiology of a subgroup of patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Increased IgM-related autoimmune responses to oxidative specific epitopes (OSEs), including malondialdehyde (MDA), oleic acid and phosphatidyl inositol (Pi), and nitroso-(NO)-adducts, including NO-tryptophan (NOW), NO-arginine and NO-cysteinyl, are frequently observed in ME/CFS. Autoimmune responses in ME/CFS may be driven by increased bacterial translocation as measured by IgM and IgA responses to LPS of gram negative bacteria.

METHODS: The aim of this study is to examine whether IgM responses to OSEs and NO-adducts are related to a better outcome as measured by the Fibromyalgia and Fatigue Rating Scale (FF). 76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine.

RESULTS: We found that use of these NAIOS was associated with highly significant reductions in initially increased IgM-mediated autoimmune responses to OSEs and NO-adducts. A greater reduction in autoimmune responses to OSEs during intake of these NAIOS was associated with a lower FF score. Reductions in IgM responses to oleic acid, MDA and Pi, but not in any of the NO-adducts, were associated with reductions in severity of illness. These associations remained significant after adjusting for possible effects of increased bacterial translocation (leaky gut).

CONCLUSIONS: Our results show that autoimmune responses to OSEs are involved in the pathophysiology of ME/CFS and that these pathways are a new drug target in a subgroup of ME/CFS patients. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of illness. Randomized controlled trials with NAIOS should be carried out in the subgroup of ME/CFS patients with initially increased autoimmune responses to OSEs.

 

Source: Maes M, Leunis JC. Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett. 2014;35(7):577-85. https://www.ncbi.nlm.nih.gov/pubmed/25617880