review – Page 27 – American ME and CFS Society

A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

Abstract:

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered.

In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

Source: Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013 Sep 30;2013:784520. doi: 10.1155/2013/784520. eCollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045534/ (Full article)

Chronic fatigue syndrome following infections in adolescents

Abstract:

PURPOSE OF REVIEW: To review the recent epidemiology, pathophysiology, and treatment of postinfectious chronic fatigue syndrome (CFS) in adolescents.

RECENT FINDINGS: Thirteen percent of adolescents (mainly women) met the criteria for CFS 6 months following infectious mononucleosis; the figure was 7% at 12 months and 4% at 24 months. Peak work capacity, activity level, orthostatic intolerance, salivary cortisol, and natural killer cell number and function were similar between adolescents with CFS following infectious mononucleosis and recovered controls. Autonomic system, oxygen consumption, peak oxygen pulse, psychological and cytokine network differences were documented between those who recovered and those who did not.

SUMMARY: The prognosis of CFS is better in adolescents than in adults. Activity level, exercise tolerance, and orthostatic testing could not distinguish patients with CFS from adolescents who have recovered from infectious mononucleosis (controls), while certain cytokine network analyses, life stress factors, and autonomic symptoms could.

Source: Katz BZ, Jason LA. Chronic fatigue syndrome following infections in adolescents. Curr Opin Pediatr. 2013 Feb;25(1):95-102. doi: 10.1097/MOP.0b013e32835c1108. https://www.ncbi.nlm.nih.gov/pubmed/23263024

Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a chronic, disabling illness that affects approximately 0.2% of the population. Non-restorative sleep despite sufficient or extended total sleep time is one of the major clinical diagnostic criteria; however, the underlying cause of this symptom is unknown.

This review aims to provide a comprehensive overview of the literature examining sleep in CFS/ME and the issues surrounding the current research findings. Polysomnographic and other objective measures of sleep have observed few differences in sleep parameters between CFS/ME patients and healthy controls, although some discrepancies do exist. This lack of significant objective differences contrasts with the common subjective complaints of disturbed and unrefreshed sleep by CFS/ME patients.

The emergence of new, more sensitive techniques that examine the microstructure of sleep are showing promise for detecting differences in sleep between patients and healthy individuals. There is preliminary evidence that alterations in sleep stage transitions and sleep instability, and other physiological mechanisms, such as heart rate variability and altered cortisol profiles, may be evident. Future research investigating the etiology of non-restorative sleep in CFS/ME may also help us to undercover the causes of non-restorative sleep and fatigue in other medical conditions.

Source: Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med. 2012 Dec 15;8(6):719-28. doi: 10.5664/jcsm.2276. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501671/ (Full article)

Chronic Fatigue Syndrome (CFS) and Cancer Related Fatigue (CRF): two “fatigue” syndromes with overlapping symptoms and possibly related aetiologies

Abstract:

In July 2010, at the Muscle Fatigue Meeting, I presented an overview of Chronic Fatigue Syndrome and Cancer Related Fatigue, emphasizing a critical interpretation of the potential association between Chronic Fatigue Syndrome and Cancer Related Fatigue and a newly discovered retrovirus: Xenotropic Murine Related Virus. Since this association was hotly debated at that time, I suggested at the Meeting that it was wrong and most likely due to the identification of the wrong virus culprit.

Today, 20 months after the Meeting, the first part of our prediction has turned out to be correct, as Xenotropic Murine Related Virus was shown to be a laboratory-created artefact. Still, the potential association of fatigue-syndromes with an infection (most likely viral) is sustained by a plethora of evidence and this overview will initially summarize data suggesting prior viral infection(s). The principal hypothesized mechanisms for both peripheral and central Chronic Fatigue Syndrome/Cancer Related Fatigue will be then summarized, also indicating plausible associations and triggering factors.

All evidence accrued so far suggests that further research work should be performed in this interesting area and in order to identify an infectious agent for Chronic Fatigue Syndrome/Cancer Related Fatigue. One candidate RNA virus, Micro-Foci inducing Virus, will be described in this overview.

Source: Rovigatti U. Chronic Fatigue Syndrome (CFS) and Cancer Related Fatigue (CRF): two “fatigue” syndromes with overlapping symptoms and possibly related aetiologies. Neuromuscul Disord. 2012 Dec;22 Suppl 3:S235-41. doi: 10.1016/j.nmd.2012.10.018. https://www.ncbi.nlm.nih.gov/pubmed/23182646

Sleep in the chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a disabling condition characterized by severe fatigue lasting for more than six months and the presence of at least four out of eight minor criteria. Sleep disturbance presenting as unrefreshing or nonrestorative sleep is one of these criteria and is very common in CFS patients. Biologically disturbed sleep is a known cause of fatigue and could play a role in the pathogenesis of CFS. However, the nature of presumed sleep impairment in CFS remains unclear. Whilst complaints of NRS persist over time, there is no demonstrable neurophysiological correlate to substantiate a basic deficit in sleep function in CFS. Polysomnographic findings have not shown to be significantly different between subjects with CFS and normal controls. Discrepancies between subjectively poor and objectively normal sleep suggest a role for psychosocial factors negatively affecting perception of sleep quality. Primary sleep disorders are often detected in patients who otherwise qualify for a CFS diagnosis. These disorders could contribute to the presence of daytime dysfunctioning. There is currently insufficient evidence to indicate that treatment of primary sleep disorders sufficiently improves the fatigue associated with CFS. Therefore, primary sleep disorders may be a comorbid rather than an exclusionary condition with respect to CFS.

Source: Mariman AN, Vogelaers DP, Tobback E, Delesie LM, Hanoulle IP, Pevernagie DA. Sleep in the chronic fatigue syndrome. Sleep Med Rev. 2013 Jun;17(3):193-9. doi: 10.1016/j.smrv.2012.06.003. Epub 2012 Oct 6. https://www.ncbi.nlm.nih.gov/pubmed/23046847

Pain in patients with chronic fatigue syndrome: time for specific pain treatment?

Abstract:

BACKGROUND: Besides chronic fatigue, patients with chronic fatigue syndrome (CFS) have debilitating widespread pain. Yet pain from CFS is often ignored by clinicians and researchers.

OBJECTIVES: To examine whether pain is a unique feature of CFS, or does it share the same underlying mechanisms as other CFS symptoms? Second, it is examined whether effective treatments for pain from CFS are currently available.

STUDY DESIGN: Narrative review covering the scientific literature up through December 2011.

SETTING: Several universities.

RESULTS: From the available literature, it is concluded that musculoskeletal factors are unlikely to account for pain from CFS. Pain seems to be one out of many symptoms related to central sensitization from CFS. This idea is supported by the findings of generalized hyperalgesia (including widespread increased responsiveness to painful stimuli) and dysfunctional endogenous analgesia in response to noxious thermal stimuli. Pain catastrophizing and depression partly account for pain from CFS. Pain increases during exercise is probably due to the lack of endogenous analgesia and activation of several genes in response to exercise in CFS. There is currently no evidence in support for the efficacy of complementary medicine in the treatment of pain from CFS. Intensive education about the biology of pain from CFS (within the framework of central sensitization) has positive short-term effects for patients with CFS, and fatigue-targeting cognitive behavioral therapy appears to be effective for pain from CFS as well.

LIMITATIONS: The role of the deficient hypothalamus-pituitary-adrenal axis in relation to pain from CFS, as well as the interactions with immune (dys)functioning require further study.

CONCLUSION: Recent research has increased our understanding of pain from CFS, including its treatment. It is advocated to optimize current CFS treatment protocols by targeting the underlying mechanism for those patients having severe pain.

Source: Nijs J, Crombez G, Meeus M, Knoop H, Damme SV, Cauwenbergh V, Bleijenberg G. Pain in patients with chronic fatigue syndrome: time for specific pain treatment? Pain Physician. 2012 Sep-Oct;15(5):E677-86. http://www.painphysicianjournal.com/linkout?issn=1533-3159&vol=15&page=E677 (Full article)

Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis

Abstract:

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained syndromes that can and often do co-occur. For this reason, some have posited that the two are part of the same somatic syndrome–examples of symptom amplification. This hypothesis would suggest that few differences exist between the two syndromes. To evaluate this interpretation, we have searched the literature for articles comparing CFS to FM, reviewing only those articles which report differences between the two. This review presents data showing differences across a number of parameters–implying that the underlying pathophysiology in CFS may differ from that of FM. We hope that our review encourages other groups to look for additional differences between CFS and FM. By continuing to preserve the unique illness definitions of the two syndromes, clinicians will be able to better identify, understand and provide treatment for these individuals.

Source: Abbi B, Natelson BH. Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis. QJM. 2013 Jan;106(1):3-9. doi: 10.1093/qjmed/hcs156. Epub 2012 Aug 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527744/ (Full article)

Biomarkers for chronic fatigue

Abstract:

Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Inflammation, immune system activation, autonomic dysfunction, impaired functioning in the hypothalamic-pituitary-adrenal axis, and neuroendocrine dysregulation have all been suggested as root causes of fatigue. The identification of objective markers consistently associated with CFS/ME is an important goal in relation to diagnosis and treatment, as the current case definitions are based entirely on physical signs and symptoms.

This review is focused on the recent literature related to biomarkers for fatigue associated with CFS/ME and, for comparison, those associated with other diseases. These markers are distributed across several of the body’s core regulatory systems. A complex construct of symptoms emerges from alterations and/or dysfunctions in the nervous, endocrine and immune systems. We propose that new insight will depend on our ability to develop and deploy an integrative profiling of CFS/ME pathogenesis at the molecular level. Until such a molecular signature is obtained efforts to develop effective treatments will continue to be severely limited.

Source: Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun. 2012 Nov;26(8):1202-10. doi: 10.1016/j.bbi.2012.06.006. Epub 2012 Jun 23. https://www.ncbi.nlm.nih.gov/pubmed/22732129

How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines

Abstract:

BACKGROUND: Despite the large number of studies emphasizing the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for people with chronic fatigue syndrome (CFS), clinicians are left wondering how exactly to apply exercise therapy to their patients with CFS. The aim of this literature review is to identify the appropriate exercise modalities (i.e. exercise duration, mode, number of treatment sessions, session length, duration of treatment, exercise intensity and whether or not to apply home exercise program) for people with CFS.

MATERIALS AND METHODS: All studies that were identified through electronic databases (PubMed and PEDro) were assessed for methodological quality by using selection criteria (Delphi score).

RESULTS: In this literature review, 12 studies fulfilled all study requirements. One study had a low methodological quality. The parameters used in the GET and CBT interventions were divided into subgroups: (i) time or symptom contingent, (ii) exercise frequency and (iii) exercise modality.

CONCLUSION: The lack of uniformity in outcome measures and CFS diagnostic criteria make it difficult to compare the findings across studies. Based on the available evidence, exercise therapy for people with CFS should be aerobic and must comprise of 10-11 sessions spread over a period of 4-5 months. A time-contingent approach is preferred over a symptom-contingent way of exercising. In addition, people with CFS can perform home exercises five times a week with an initial duration of 5-15 min per exercise session. The exercise duration can be gradually increased up to 30 min.

Comment in:

Graded exercise therapy (GET)/cognitive behavioural therapy (CBT) is often counterproductive in myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). [Eur J Clin Invest. 2012]

Exercise and chronic fatigue syndrome: maximize function, minimize post-exertional malaise. [Eur J Clin Invest. 2012]

Objective compliance and outcome measures should be used in trials of exercise interventions for Chronic Fatigue Syndrome. [Eur J Clin Invest. 2012]

Source: Van Cauwenbergh D De Kooning M, Ickmans K, Nijs J. How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines. Eur J Clin Invest. 2012 Oct;42(10):1136-44. doi: 10.1111/j.1365-2362.2012.02701.x. Epub 2012 Jun 23. https://www.ncbi.nlm.nih.gov/pubmed/22725992

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome

Abstract:

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors.

Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve.

Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis.

This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

Source: Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013 Dec;28(4):523-40. doi: 10.1007/s11011-012-9324-8. Epub 2012 Jun 21. https://www.ncbi.nlm.nih.gov/pubmed/22718491