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Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of...
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Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms

A special issue of Medicina (ISSN 1648-9144). This special issue belongs to the section "Neurology".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 44108

Special Issue Editor

Dr. Olli J. Polo

E-Mail Website
Guest Editor
Bragée ME/CFS Center, Stockholm, Sweden
Interests: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; post-COVID; long covid; brain fog; hypothesis; mechanism; pathophysiology; patient history; clinical signs; medical treatment

Special Issue Information

Dear Colleagues,

Chronic fatigue syndromes (ICD-10 code G93.3) are one of the major mysteries of current medical science. While myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is still a very much debated condition, a similar set of post-viral fatigue symptoms is now appearing in the aftermath of COVID-19. There is no known cause or effective treatment. Therefore, the need for understanding the etiology and pathophysiologic mechanisms of fatigue syndromes has never before been as timely and urgent as today. Depending on the area of expertise, several theories of pathogenesis and pathophysiology have been proposed. In addition to earlier psychological theories, chronic (viral) infections, systemic inflammation, autoimmune diseases, and disorders of the autonomic nervous system dysautonomia are the most commonly proposed ones. Despite intensive current research and promising initiatives, none of the approaches has so far managed to result in effective therapies to cure or even systematically control the debilitating symptoms.

Epidemic outbreaks of ME/CFS have been described before. However, there is a risk that COVID-19 becomes the first pandemic that is followed by post-viral fatigue of a global range. This would result in significant individual suffering, a burden on healthcare systems, and decreased productivity of economies. We absolutely need to share and combine all our efforts that could contribute to further understanding the disease mechanisms, to get control over the current and future chronic fatigue pandemics.

More research into fatigue syndromes is urgently needed. Significant research is possible only if we have innovative theories or a hypothesis to test. Every clinician who has solid knowledge around basic sciences, an observational eye, and the ability to pay careful attention to patients’ symptoms and responses to medical treatments and nonmedical interventions may develop their own understanding of ME/CFS or post-COVID syndrome. If you have a novel idea regarding this issue, as well as the resources to investigate it further and perhaps submit a patent application for a potential treatment, then I would encourage you to do just that. However, if you still think that you have a good understanding or an idea arising from your clinical observations but do not think you could take it further by yourself, perhaps because the diagnostic testing you are proposing does not even exist yet, then you should consider that sharing your experience and thoughts could inspire other clinicians or researchers to combine your idea with their experience or take it forward to scientific testing or methodological development, for the benefit of all.

Therefore, I invite you to (1) describe those patient histories, status findings, laboratory tests, clinical investigations, and perhaps with surprising treatment outcomes that you are able to (2) evaluate against your literature review and combine into a unifying hypothesis of potential disease mechanisms. It could be an ambitious unifying hypothesis or just a smaller thought linking two or more things together. You may share potential (even hypothetical) biomarkers for diagnostic testing. Finally, based on your hypothesis, you may propose a treatment that either cures or alleviates the symptoms of chronic fatigue.

For your own credit, you may provide a name for your innovative hypothesis so that those who may subsequently test it can better refer to your innovation. Use of imagination, the most powerful innovation tool of human beings, is encouraged. However, to guarantee scientific credibility, your idea must arise from clinical observations. You should test your proposal against the current body of evidence (review section) before you liberate your creative mind for future projections.

I solicit papers addressing ME/CFS, post-COVID/long COVID syndrome or other conditions where long-term fatigue is a central clinical complaint. I encourage you to report on symptoms or signs that you think have so far received too little attention. You may report their frequency in your patient population and put them into a meaningful context of plausible disease mechanisms. You may present a single symptom, a single case, a set of symptoms or a series of cases that have inspired your hypothesis.

Dr. Olli J. Polo
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Medicina is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Chronic fatigue syndromes
  • Myalgic encephalomyelitis
  • Cognitive disorders
  • Fibromyalgia
  • Chronic pain
  • Sleep disorder
  • Insomnia
  • Depression
  • Anxiety
  • Viral infection
  • Whiplash Injury
  • Traumatic Brain Injury
  • Ehlers-Danlos Syndrome (EDS)
  • Hypermobility Spectrum Disorder (HSD)
  • Posttraumatic Stress Disorder (PTSD)

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Published Papers (5 papers)

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Research

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11 pages, 818 KiB  
Article
Psychogenic Pseudosyncope: Real or Imaginary? Results from a Case-Control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients
by C. (Linda) M. C. van Campen and Frans C. Visser
Medicina 2022, 58(1), 98; https://doi.org/10.3390/medicina58010098 - 9 Jan 2022
Cited by 5 | Viewed by 5644
Abstract
Background and objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Exact numbers on syncopal [...] Read more.
Background and objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Exact numbers on syncopal spells especially if they are on a weekly or even daily basis are not described. Although not a frequent phenomenon, this symptomatology is of very high burden to the patient if present. To explore whether patients with very frequent (pre)syncope spells diagnosed elsewhere with conversion or psychogenic pseudosyncope (PPS) might have another explanation of their fainting spells than behavioral psychiatric disorders, we performed a case–control study comparing ME/CFS patients with and without PPS spells. Methods and results: We performed a case–control study in 30 ME/CFS patients diagnosed elsewhere with PPS and compared them with 30 control ME/CFS patients without syncopal spells. Cases were gender, age and ME/CFS disease duration matched. Each underwent a tilt test with extracranial Doppler measurements for cerebral blood flow (CBF). ME/CFS cases with PPS had a significant larger CBF reduction at end tilt than controls: 39 (6)% vs. 25 (4)%; (p < 0.0001). Cases had more severe disease compared with controls (chi-square p < 0.01 and had a p = 0.01) for more postural orthostatic tachycardia syndrome in cases compared with controls. PETCO2 end-tilt differed also, but the magnitude of difference was smaller than compared with the CBF reduction: there were no differences in heart rate and blood pressure at either end-tilt testing period. Compared with the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 25 (5) mmHg versus 29 (4) mmHg (p < 0.005). Conclusions: This study demonstrates that in ME/CFS patients suspected of having PPS, or conversion, CBF measurements end-tilt show a large decline compared with a control group of ME/CFS patients. Therefore, hypoperfusion offers an explanation of the orthostatic intolerance and syncopal spells in these patients, where it is clear that origin might not be behavioral or psychogenic, but have a clear somatic pathophysiologic background. Full article
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)
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11 pages, 3063 KiB  
Article
Compression Stockings Improve Cardiac Output and Cerebral Blood Flow during Tilt Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients: A Randomized Crossover Trial
by C. (Linda) M. C. van Campen, Peter C. Rowe and Frans C. Visser
Medicina 2022, 58(1), 51; https://doi.org/10.3390/medicina58010051 - 29 Dec 2021
Cited by 6 | Viewed by 5065
Abstract
Background and Objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Limited data are available to [...] Read more.
Background and Objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Limited data are available to guide the treatment of OI in ME/CFS patients. We and others have previously described patient-reported subjective improvement in symptoms using compression stockings. We hypothesized that these subjective reports would be accompanied by objective hemodynamic improvements. Materials and Methods: We performed a randomized crossover trial in 16 ME/CFS patients. Each underwent two 15-min head-up tilt table tests, one with and one without wearing knee-high compression stockings that provided 20–25 mm Hg compression. The order of the tests was randomized. We measured heart rate and blood pressure as well as cardiac output and cerebral blood flow (CBF) using extracranial Doppler of the internal carotid and vertebral arteries. Results: There were no differences in supine measurements between the 2 baseline measurements. There were no differences in heart rate and blood pressure at either end-tilt testing period. Compared to the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 15 (4)% versus 27 (6)% (p < 0.0001), as was the mean percentage CBF reduction, 14 (4)% versus 25 (5)% (p < 0.0001). Conclusion: In ME/CFS patients with orthostatic intolerance symptoms, cardiac output and CBF are significantly reduced during a tilt test. These abnormalities were present without demonstrable heart rate and blood pressure changes and were ameliorated by the use of compression stockings. Full article
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)
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18 pages, 3484 KiB  
Article
Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by C. (Linda) M. C. van Campen, Peter C. Rowe and Frans C. Visser
Medicina 2022, 58(1), 28; https://doi.org/10.3390/medicina58010028 - 24 Dec 2021
Cited by 42 | Viewed by 16362
Abstract
Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, [...] Read more.
Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS. Full article
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)
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Review

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8 pages, 610 KiB  
Review
Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach
by Klaus J. Wirth and Carmen Scheibenbogen
Medicina 2022, 58(3), 419; https://doi.org/10.3390/medicina58030419 - 12 Mar 2022
Cited by 31 | Viewed by 9947
Abstract
Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there [...] Read more.
Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs. Full article
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)
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10 pages, 4836 KiB  
Review
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Neurological Entity?
by Iñigo Murga Gandasegui, Larraitz Aranburu Laka, Pascual-Ángel Gargiulo, Juan-Carlos Gómez-Esteban and José-Vicente Lafuente Sánchez
Medicina 2021, 57(10), 1030; https://doi.org/10.3390/medicina57101030 - 27 Sep 2021
Cited by 16 | Viewed by 5637
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis. Our objective is to review the evidence in neuroimaging and [...] Read more.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis. Our objective is to review the evidence in neuroimaging and dysautonomia evaluation in order to support the neurological involvement and to find biomarkers serving to identify and/or monitor the pathology. The symptoms typically appear acutely, although they can develop progressively over years; an essential trait for diagnosis is “central” fatigue together with physical and/or mental exhaustion after a small effort. Neuroimaging reveals various morphological, connectivity, metabolic, and functional alterations of low specificity, which can serve to complement the neurological study of the patient. The COMPASS-31 questionnaire is a useful tool to triage patients under suspect of dysautonomia, at which point they may be redirected for deeper evaluation. Recently, alterations in heart rate variability, the Valsalva maneuver, and the tilt table test, together with the presence of serum autoantibodies against adrenergic, cholinergic, and serotonin receptors were shown in a subgroup of patients. This approach provides a way to identify patient phenotypes. Broader studies are needed to establish the level of sensitivity and specificity necessary for their validation. Neuroimaging contributes scarcely to the diagnosis, and this depends on the identification of specific changes. On the other hand, dysautonomia studies, carried out in specialized units, are highly promising in order to support the diagnosis and to identify potential biomarkers. ME/CFS orients towards a functional pathology that mainly involves the autonomic nervous system, although not exclusively. Full article
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)
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