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)

 

Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis

Abstract:

BACKGROUND: Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care.

METHODS: A qualitative study with open interviews was employed. In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26-59 years old was recruited from a population diagnosed at a fatigue outpatient clinic.

RESULTS: The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms. Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants’ experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability.

CONCLUSIONS: Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible.

 

Source: Stormorken E, Jason LA, Kirkevold M. Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis. BMC Nurs. 2015 Nov 28;14:64. doi: 10.1186/s12912-015-0115-5. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662830/ (Full article)

 

The Nature of Fatigue in Chronic Fatigue Syndrome

Abstract:

In this article, we report the findings of our study on the nature of fatigue in patients diagnosed with chronic fatigue syndrome. Using ethnoscience as a design, we conducted a series of unstructured interviews and card sorts to learn more about how people with chronic fatigue syndrome describe fatigue. Participants (N = 14) described three distinct domains: tiredness, fatigue, and exhaustion. Most participants experienced tiredness prior to diagnosis, fatigue during daily life, and exhaustion after overexertion. We also discuss participants’ ability to adapt to a variety of stressors and prevent shifts to exhaustion, and relate our findings to stress theory and other current research. Primary strategies that promoted adaptation to stressors included pacing and extended rest periods. These findings can aid health care professionals in detecting impending shifts between tiredness, fatigue, and exhaustion and in improving adaptive strategies, thereby improving quality of life.

© The Author(s) 2015.

 

Source: Olson K, Zimka O, Stein E. The Nature of Fatigue in Chronic Fatigue Syndrome. Qual Health Res. 2015 Oct;25(10):1410-22. doi: 10.1177/1049732315573954. Epub 2015 Feb 26. https://www.ncbi.nlm.nih.gov/pubmed/25721719

 

Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue

Abstract:

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation.

In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses.

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.

These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

 

Source: Miller AH, Jones JF, Drake DF, Tian H, Unger ER, Pagnoni G. Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue. PLoS One. 2014 May 23;9(5):e98156. doi: 10.1371/journal.pone.0098156. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032274/ (Full article)

 

Fatigue heralding multiple sclerosis

Abstract:

BACKGROUND: Fatigue is a common symptom in multiple sclerosis (MS) and is an important determinant of overall well-being and disability.

OBJECTIVE: To assess the frequency with which fatigue precedes the diagnosis of MS using a retrospective database analysis.

METHODS: Between January 1, 2003 and September 30, 2008, patients diagnosed with fatigue with and without fatigue-related medications within a 3-year period prior to newly diagnosed MS were identified from the MarketScan Databases. All statistical analysis was performed using SAS.

RESULTS: Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS. One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed medication for fatigue.

CONCLUSION: This study demonstrates that fatigue may herald MS, often by years. A careful history for transient neurological symptoms and a physical examination is warranted in any patient presenting with fatigue.

 

Source: Berger JR, Pocoski J, Preblick R, Boklage S. Fatigue heralding multiple sclerosis. Mult Scler. 2013 Oct;19(11):1526-32. doi: 10.1177/1352458513477924. Epub 2013 Feb 25. https://www.ncbi.nlm.nih.gov/pubmed/23439577

 

A Chronic Fatigue Syndrome (CFS) severity score based on case designation criteria

Abstract:

BACKGROUND: Chronic Fatigue Syndrome case designation criteria are scored as physicians’ subjective, nominal interpretations of patient fatigue, pain (headaches, myalgia, arthralgia, sore throat and lymph nodes), cognitive dysfunction, sleep and exertional exhaustion.

METHODS: Subjects self-reported symptoms using an anchored ordinal scale of 0 (no symptom), 1 (trivial complaints), 2 (mild), 3 (moderate), and 4 (severe). Fatigue of 3 or 4 distinguished “Fatigued” from “Not Fatigued” subjects. The sum of the 8(Sum8) ancillary criteria was tested as a proxy for fatigue. All subjects had history and physical examinations to exclude medical fatigue, and ensure categorization as healthy or CFS subjects.

RESULTS: Fatigued subjects were divided into CFS with ≥4 symptoms or Chronic Idiopathic Fatigue (CIF) with ≤3 symptoms. ROC of Sum8 for CFS and Not Fatigued subjects generated a threshold of 14 (specificity=0.934; sensitivity=0.928). CFS (n=256) and CIF (n=55) criteria were refined to include Sum8≥14 and ≤13, respectively. Not Fatigued subjects had highly skewed Sum8 responses. Healthy Controls (HC; n=269) were defined by fatigue≤2 and Sum8≤13. Those with Sum8≥14 were defined as CFS-Like With Insufficient Fatigue Syndrome (CFSLWIFS; n=20). Sum8 and Fatigue were highly correlated (R(2)=0.977; Cronbach’s alpha=0.924) indicating an intimate relationship between symptom constructs. Cluster analysis suggested 4 clades each in CFS and HC. Translational utility was inferred from the clustering of proteomics from cerebrospinal fluid.

CONCLUSIONS: Plotting Fatigue severity versus Sum8 produced an internally consistent classifying system. This is a necessary step for translating symptom profiles into fatigue phenotypes and their pathophysiological mechanisms.

 

Source: Baraniuk JN, Adewuyi O, Merck SJ, Ali M, Ravindran MK, Timbol CR, Rayhan R, Zheng Y, Le U, Esteitie R, Petrie KN. A Chronic Fatigue Syndrome (CFS) severity score based on case designation criteria. Am J Transl Res. 2013;5(1):53-68. Epub 2013 Jan 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560481/ (Full article)

 

Predictors of Fatigue among Patients with Chronic Fatigue Syndrome

Abstract:

Activity logs involve patients writing down their activities over one or more days. Several studies have found these data collection instruments to accurately describe activities of patients with chronic fatigue syndrome (CFS). The purpose of this study was to utilize the repeated measures available on the ACTRE to evaluate predictors of fatigue at a given timepoint.

A random intercept model was tested with the following variables predicting current fatigue: past fatigue (30 mins. prior), current category of activity (e.g., resting, work, recreation, etc.), past category of activity (30 mins. prior), the interaction of past fatigue and past activity, and TH2/TH1 immune shift. These findings and others suggest that activity logs can provide investigators and clinicians with valuable sources of data for understanding patterns of behavior and activity among patients with CFS.

 

Source: Jason LA, Brown M, Evans M, Brown A. Predictors of Fatigue among Patients with Chronic Fatigue Syndrome. J Hum Behav Soc Environ. 2012 Oct 1;22(7):822-833. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955704/ (Full article)

 

The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is a debilitating fatigue illness that has unknown etiology and lacks an objective diagnostic marker.

OBJECTIVE: To examine the metabolic component of CFS to determine if practitioners can use serum NAD(P)H concentration measurements to monitor metabolism and fatigue status in patients with CFS.

DESIGN: The research team conducted a case-control study, comparing a group of patients who were diagnosed with CFS with a control group of healthy subjects. The team obtained venous blood samples from fasting patients to examine the serum NAD(P)H concentrations.

SETTING: The study occurred at the Riordan Clinic in Witchita, Kansas.

PARTICIPANTS: The study included 44 CFS patients at the Riordan Clinic and 30 healthy control participants. The CFS patients presented a spectrum of symptoms that had existed for at least 6 months: new, unexplained, persistent, or relapsing chronic fatigue that bed rest did not resolve and that was severe enough to reduce daily activity significantly by 50% in conjunction with headache, muscle pain, pain in multiple joints, and unrefreshing sleep. In the control group, the research team enrolled subjects without diagnosis of disease or injury.

OUTCOME MEASURES: The research team determined levels of serum reduced nicotinamide adenine dinucleotides (NADH and NAD[P]H) by measuring serum fluorescence emission at 450 nm. The team then conducted sensitivity and specificity analyses. Results NAD(P)H concentrations in serum of CFS participants averaged 8.0 ± 1.4 (standard deviation [SD]) nmol/mL, while those in the healthy controls averaged 10.8 ± 0.8 (SD) nmol/mL, a statistically significant difference. Using a cut-off concentration of 9.5 nmol/mL, the research team attained a sensitivity of 0.73 and a specificity of 1.0. An analysis of receiver-operator characteristics yielded an area under the curve of 0.9. The research team compared serum NAD(P)H to several endocrine and metabolic lab parameters. Serum NAD(P)H was directly correlated with serum CoQ10 levels and inversely correlated with urine hydroxyhemopyrrolin-2-one levels.

CONCLUSIONS: Based on these findings, the research team proposed using serum NAD(P)H, measured as an intrinsic serum-fluorescence emission, to monitor metabolism and fatigue status in patients with CFS. Following patients NAD(P)H levels over time may aid in selecting therapeutic strategies and monitoring treatment outcomes.

 

Source: Mikirova N, Casciari J, Hunninghake R. The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission. Altern Ther Health Med. 2012 Jan-Feb;18(1):36-40. https://www.ncbi.nlm.nih.gov/pubmed/22516851

 

Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes

Excerpt:

Muscle fatigue and pain are among the most common complaints at emergency rooms and clinics across the country. Fatigue and pain are often acute, remitting spontaneously or appearing to be attenuated by a variety of drugs and treatment modalities.

In spite of these remissions, popular magazines (e.g., Time) estimate that each year Americans spend over $30 billion on herbal remedies and $50 billion on alternative therapies to treat symptoms that include muscle pain and fatigue. These statistics indicate that even acute muscle pain and fatigue are serious health problems that are not adequately addressed by current medical practice. Occasionally, muscle pain and fatigue take on a chronic nature, leading to syndromes including chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS)—devastating conditions characterized by continuing, debilitating fatigue, which is made worse by even mild exercise in the case of CFS and by chronic widespread pain (CWP) with a particular emphasis in the muscles, which can prevent most or all activities in the case of FMS.

Both of these conditions are frequently associated with each other and with a variety of other illnesses, such as temporomandibular disorder (TMD), irritable bowel syndrome (IBS), and multiple chemical sensitivity. These syndromes destroy lives, respond poorly to current treatment strategies, and can lead to exhaustion of the financial resources of afflicted patients. Together, these disorders affect 7 to 20 million people in the United States each year, as reported by various authorities (Reeves et al. 2007). Clearly, patients with these syndromes deserve a concerted research effort to understand, treat, and eventually cure these illnesses. In contrast to cutaneous pain, which has been thoroughly studied and is comparatively well understood, the molecular mechanisms for muscle pain are still unknown.

Even more enigmatic is the symptom of debilitating fatigue. Mosso, in his compendious volume on the subject a century ago, remarked that all cultures seem to have just one word for fatigue (Mosso 1904). Yet fatigue describes many conditions, including failure of muscle fibers to shorten normally, deficient motor command signals, feelings of tiredness, heaviness, pressure, and weakness from muscles, and a feeling of mental fatigue that impedes concentration and performance of conceptual tasks.

The subject of most physiological investigations of fatigue has been voluntary muscle contraction. Decreased function causing failure of voluntary muscle contraction can occur at all levels of the neuromuscular system, including the motor cortex, signaling to motoneurons, motoneuron signals to the muscle, excitation-contraction coupling in the muscle, and actin-myosin filament interactions. However, the most common failure is a decrease in the motor command signal from the motor cortex (see recent reports and reviews by Bellinger et al. 2008; Gibson et al. 2003; Noakes et al. 2005; St Clair and Noakes 2004).

A recent review suggests that failures in voluntary muscle contraction are most often caused by a central comparator that integrates homeostatic inputs from many physiological systems and shuts down motor commands when energy resources are threatened (Noakes 2007). One of the homeostatic inputs is suggested to “originate from a difference between subconscious representations of baseline physiological homeostatic state and the state of physiological activity induced by physical activity, which creates a second order representation which is perceived by consciousnessproducing structures as the sensation of fatigue” (Gibson et al. 2003, page 174).

We suggest that there is a simpler sensation of fatigue that is triggered by inputs from specific receptors that are sensitive to metabolites produced by muscle contraction. We further propose that this elementary sensation is transduced, conducted, and perceived within a unique sensory system with properties analogous to other sensory modalities such as pain. We call it the “sensation of muscle fatigue.”

Copyright © 2010 by Taylor and Francis Group, LLC.

 

Source: Light AR, Vierck CJ, Light KC. Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. Chapter 11. Frontiers in Neuroscience. https://www.ncbi.nlm.nih.gov/books/NBK57253/ (Full chapter)

 

Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study

Abstract:

Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms.

Six hundred and thirty-three healthy females (age 14.63±1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 4½ years thereafter.

Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time.

Higher interferon (IFN)-γ, higher IFN-γ/interleukin (IL)-4 ratio, lower tumor necrosis factor-α and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression.

In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: ter Wolbeek M, van Doornen LJ, Kavelaars A, Tersteeg-Kamperman MD, Heijnen CJ. Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study. Brain Behav Immun. 2011 Aug;25(6):1249-55. doi: 10.1016/j.bbi.2011.04.015. Epub 2011 Apr 28. https://www.ncbi.nlm.nih.gov/pubmed/21549830