Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogenous disorder of multiple disabling symptoms with complex manifestations. Network analysis is a statistical and interrogative methodology to investigate the prevalence of symptoms (nodes) and their inter-dependent (inter-nodal) relationships. In the present study, we explored the co-occurrence of symptoms in a cohort of Polish CFS patients using network analysis.

A total of 110 patients with CFS were examined (75 females). The mean age of the total sample was 37.93 (8.5) years old while the mean duration of symptoms in years was 4.4 (4). Post-exertional malaise (PEM) was present in 75.45% of patients, unrefreshing sleep was noted in 89.09% and impaired memory or concentration was observed in 87.27% of patients. The least prevalent symptom was tender cervical or axillary lymph nodes, noted in 34.55% of the total sample.

Three of the most densely connected nodes were the total number of symptoms, sore throat and PEM. PEM was positively related with impairment in memory or concentration. Both PEM and impairment in memory or concentration presence are related to more severe fatigue measured by CFQ and FIS. PEM presence was positively related with the presence of multi-joint pain and negatively with tender lymph nodes and muscle pain. Sore throat was related with objective and subjective autonomic nervous system impairment. This study helps define symptom presentation of CFS with the pathophysiology of specific systems and links with multidisciplinary contemporary molecular pathology, including comparative MRI.

Source: Kujawski S, Słomko J, Newton JL, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S, Zalewski P. Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome. Int J Environ Res Public Health. 2021 Oct 13;18(20):10736. doi: 10.3390/ijerph182010736. PMID: 34682478; PMCID: PMC8535251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535251/ (Full text)

Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review

Abstract:

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS.

In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

Source: Du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. Int J Environ Res Public Health. 2021 Oct 12;18(20):10708. doi: 10.3390/ijerph182010708. PMID: 34682454; PMCID: PMC8535478. https://pubmed.ncbi.nlm.nih.gov/34682454/ (Full text)

Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study

Abstract:

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months;

(2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced;

(3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation;

(4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores.

Source: Balinas C, Eaton-Fitch N, Maksoud R, Staines D, Marshall-Gradisnik S. Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study. Int J Environ Res Public Health. 2021 Oct 11;18(20):10614. doi: 10.3390/ijerph182010614. PMID: 34682360; PMCID: PMC8535742.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535742/ (Full text)

Pain-related post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A systematic review and three-level meta-analysis

Abstract:

Objective: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM) are two debilitating, moderately comorbid illnesses in which chronic musculoskeletal pain symptoms are prevalent. These individuals can experience post-exertional malaise (PEM), a phenomenon where symptom severity is worsened 24hr or longer following physical stress, but the pain-related component of PEM is not well characterized.

Design: Systematic review and meta-analysis.

Methods: Case-control studies involving adults with ME/CFS or FM and measuring pain symptoms before and after exposure to a standardized aerobic exercise test were included. Hedges’ d effect sizes were aggregated using random effects models and potential moderators were explored with meta-regression analysis. Results were adjusted for nesting effects using three-level modeling.

Results: Forty-five effects were extracted from 15 studies involving 306 patients and 292 healthy controls. After adjusting for nesting effects, we observed a small-to-moderate effect indicating higher post-exercise pain in patients than controls (Hedges’ d=0.42; 95% CI: 0.16, 0.67). The mean effect was significantly moderated by pain measurement timepoint (b = -0.19, z = -2.57, P = 0.01) such that studies measuring pain 8-72hr post-exercise showed larger effects (d = 0.71, 95% CI = 0.28-1.14) than those measuring pain 0-2hr post-exercise (d = 0.32, 95% CI = 0.10-0.53).

Conclusions: People with ME/CFS and FM experience small-to-moderate increases in pain severity following exercise which confirms pain as a component of PEM and emphasizes its debilitating impact in ME/CFS and FM. Future directions include determining mechanisms of pain-related PEM and developing exercise prescriptions that minimize symptom exacerbation in these illnesses.

Source: Barhorst EE, Boruch AE, Cook DB, Lindheimer JB. Pain-related post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A systematic review and three-level meta-analysis. Pain Med. 2021 Oct 20:pnab308. doi: 10.1093/pm/pnab308. Epub ahead of print. PMID: 34668532. https://pubmed.ncbi.nlm.nih.gov/34668532/

Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Objective: Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.

Methods: 60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).

Results: End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.

Conclusions: During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.

Significance: The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.

Source: van Campen CLMC, Rowe PC, Visser FC. Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients. Clin Neurophysiol Pract. 2021 Sep 23;6:245-255. doi: 10.1016/j.cnp.2021.09.001. PMID: 34667909; PMCID: PMC8505270. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505270/  (Full text)

The 1918 Influenza Pandemic: Back to the Future?

Abstract:

Background: It is just over a century since the 1918 flu pandemic, sometimes referred to as the “mother” of pandemics. This brief retrospective of the 1918 pandemic is taken from the viewpoint of the current SARS-CoV-2/COVID-19 pandemic and is based on a short lecture given during the 2021 Virtual Congress of the ERA-EDTA.

Summary: This review summarizes and highlights some of the earlier pandemic’s salient features, some parallels with today, and some potential learnings, bearing in mind that the flu pandemic occurred over 100 years ago at a time of major turmoil during the climax to WWl, and with limited medical expertise and knowledge, research facilities, or well-structured and resourced healthcare services. While there is little or no information on renal complications at the time, or an effective treatment, some observations in relation to COVID-19 and vaccination are included.

Key Messages: Lessons are difficult to draw from 1918 other than the importance and value of non-pharmaceutical measures to limit viral transmission. While the economic impact of the 1918 pandemic was significant, as it is now with COVID-19, subsequent economic analysis has shown that protecting public health and preserving economic activity are not mutually exclusive. Both H1N1 and SARS-CoV-2 viruses are neurotropic and may cause chronically debilitating neurological diseases, including conditions such as encephalitis lethargica (still debated) and myalgic encephalomyelitis (chronic fatigue syndrome), respectively. Although coronavirus and influenza viral infections have some similarities, they are certainly not the same, as we are realising, and future infectious pandemics may still surprise us, but being “forewarned is forearmed.”

Source: Unwin RJ. The 1918 Influenza Pandemic: Back to the Future? Kidney Blood Press Res. 2021 Oct 18:1-8. doi: 10.1159/000519288. Epub ahead of print. PMID: 34662882. https://pubmed.ncbi.nlm.nih.gov/34662882/ 

Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS) represents a significant public health challenge given the presence of many unexplained patient symptoms. Research has shown that many features in ME/CFS may result from a dysfunctional autonomic nervous system (ANS). We explored the role of the cortical autonomic network (CAN) involved in higher-order control of ANS functioning in 34 patients with ME/CFS and 34 healthy controls under task-free conditions.

All participants underwent resting-state quantitative electroencephalographic (qEEG) scalp recordings during an eyes-closed condition. Source analysis was performed using exact low-resolution electromagnetic tomography (eLORETA), and lagged coherence was used to estimate intrinsic functional connectivity between each node across 7 frequency bands: delta (1-3 Hz), theta (4-7 Hz), alpha-1 (8-10 Hz), alpha-2 (10-12 Hz), beta-1 (13-18 Hz), beta-2 (19-21 Hz), and beta-3 (22-30 Hz). Symptom ratings were measured using the DePaul Symptom Questionnaire and the Short Form (SF-36) health survey. Graph theoretical analysis of weighted, undirected connections revealed significant group differences in baseline CAN organization.

Regression results showed that cognitive, affective, and somatomotor symptom cluster ratings were associated with alteration to CAN topology in patients, depending on the frequency band. These findings provide evidence for reduced higher-order homeostatic regulation and adaptability in ME/CFS. If confirmed, these findings address the CAN as a potential therapeutic target for managing patient symptoms.

Source: Zinn MA, Jason LA. Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Psychophysiol. 2021 Oct 15:S0167-8760(21)00900-4. doi: 10.1016/j.ijpsycho.2021.10.004. Epub ahead of print. PMID: 34662673. https://pubmed.ncbi.nlm.nih.gov/34662673/

The ‘medically unexplained symptoms’ syndrome concept and the cognitive-behavioural treatment model

Abstract:

The American Psychiatric Association’s, 2013 DSM-5 abandoned the use of the term ‘medically unexplained symptoms’ for non-neurological disorders. In the UK, treatments for various medical illnesses with unexplained aetiology, such as chronic fatigue syndrome, irritable bowel syndrome and fibromyalgia, continue to fall under an MUS umbrella with cognitive behavioural therapy promoted as a primary therapeutic approach. In this editorial, we comment on whether the MUS concept is a viable diagnostic term, the credibility of the cognitive-behavioural MUS treatment model, the necessity of practitioner training and the validity of evidence of effectiveness in routine practice.

Source: Scott MJ, Crawford JS, Geraghty KJ, Marks DF. The ‘medically unexplained symptoms’ syndrome concept and the cognitive-behavioural treatment model. Journal of Health Psychology. September 2021. doi:10.1177/13591053211038042 https://journals.sagepub.com/doi/10.1177/13591053211038042 (Full text)

Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic

Abstract:

Purpose: This manuscript reviews the experience of a University Immunology clinic with the evaluation of patients with idiopathic fatigue and exercise intolerance for the presence of metabolic disorders. Laboratory, biochemical and genetic studies were utilized in the evaluation.

Recent Findings: Of the 372 patients evaluated, 95% were found to have a treatable metabolic disorder. A defect in the glycogen storage pathway was found in 78 patients. Mitochondrial disorders were found in 258 patients. Myoadenylate deaminase deficiency was found in 7 patients. Various congenital myopathies were identified in 11 patients. Inflammatory myopathies were identified in 25 patients, 6 of whom had normal muscle enzymes on the initial evaluation.

Summary: The majority of patients (95%) referred with idiopathic fatigue and exercise intolerance after extensive evaluations were found to have underlying metabolic dysfunction. Frequently associated problems included gastrointestinal dysmotility disorders, recurrent infections, Raynaud’s, migraine headaches and various autoimmune diseases. Most patients showed symptomatic improvement with treatment of their metabolic dysfunction.

Source: Julian L A, Paul I, Molly M, John B, Lucia B. Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic. Arch Rheum & Arthritis Res. 1(1): 2020. ARAR.MS.ID.000505. https://irispublishers.com/arar/fulltext/Investigating-Fatigue-and-Exercise-Intolerance-in-a-University.ID.000505.php (Full text)

Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people.

Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS.

This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.

Source: Van Oosterwijck J, Marusic U, De Wandele I, Meeus M, Paul L, Lambrecht L, Moorkens G, Danneels L, Nijs J. Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Sep 30;10(19):4527. doi: 10.3390/jcm10194527. PMID: 34640544. https://pubmed.ncbi.nlm.nih.gov/34640544/