EMEA News Q1 2024

The authors initially claim that the current public narrative on severe, persistent fatigue conditions are “most commonly expressed by campaigners concerned with chronic fatigue syndrome (CFS/myalgic encephalomyelitis (ME/CFS)), but more recently by those writing about post-covid-19 condition”. These “campaigners” include the Institute of Medicine and their 400-page review of ME/CFS1 and the recent guidelines by the National Institute for Health and Care Excellence2. The prognosis of ME is not a question of “narratives” but of good, transparent, and reproducible empiric evaluation. The results of research are consistent, suggesting low rates of full recovery of between 5-10 % for adults3-6.

In claiming a lack of specificity in the newer criteria including post exertional malaise (PEM) as a mandatory symptoms2,7, the authors are unaware of recent research, finding lower thresholds for lactate production8 and lower oxygen extraction9 during exercise in ME/CFS-patients as contributors to ME/CFS exertional intolerance-and thus to PEM. Other publications have identified mitochondrial dysfunction to be a likely explanation for PEM10 and have shown a correlation between severity and mitochondrial damage10,11.

The authors propose an alternative explanation based on questionable scientific evidence that purports to offer realistic hope of improvement and recovery. This scientific evidence comprises a study in 19 female CFS patients and 21 normal healthy controls showing significant changes in a single measure of heart rate variability after cognitive therapy12, and a study of long-term follow-up in children and young adults13 that may have a much better prognosis. However, the latter study relies on limited data and is contradicted by a more recent and larger study14. Cognitive treatment plays a limited role in ME/CFS as pointed out in the NICE-guidelines2. In lumping patients with a diagnosis of ME/CFS in to one non-specific group of patients with fatigue clearly demonstrates the authors’ limited clinical and scientific experience in ME/CFS and the fact that several of the manifestations of this disease may be alleviated by targeted treatment15-17.

The authors state that the approach often recommended by the public narrative of inactivity, isolation, and sensory deprivation, risks worsening symptoms and associated disability. Firstly, such a statement discloses the authors’ lack of clinical experience with the range of severity and phenotypes in ME/CFS requiring modifications in the therapeutic approach. Secondly, it is an unsubstantiated claim (no references) and for the potential risks, the authors refer to a meta-analysis on bed rest as a primary treatment in conditions such as acute low back pain, preeclampsia, and myocardial infarction15 and to an unpublished study on long-term sensory deprivation related to space flights16. Sensory deprivation is not a choice but a necessity in ME/CFS-patients due to the general increased sensitivity of the nervous system to afferent input secondary to neuro-inflammation. Symptoms of neuroinflammation are essential in the diagnosis of ME/CFS and different imaging techniques have shown neuroinflammation to be present in several studies17,18 and that neuroinflammation is a common denominator in ME/CFS and long-COVID19.

In the “Oslo Declaration’s” justification for a new perspective, the authors refer to chronic pain, fibromyalgia, and post COVID syndrome for support, but recent advances do not support their narrative.

The “Oslo Declaration” is flawed, and the dismissal of biological evidence as non-specific associations is bewildering, with the authors seeking to replace it with a biopsychosocial model entirely based on associations. A recent study in fibromyalgia has demonstrated that patient autoantibodies mediate the sensory, motor, and anatomical symptoms and signs that patients present with20. Similarly, studies have revealed pathophysiological mechanisms including immune cell dysregulation and altered cortisol levels in post COVID patients21. The authors claim “After 40 years of research into CFS/ME … neither a specific biological defect or pathology, nor a specific biomarker, has been identified”. It is estimated that at least 10,000 scientific papers have been published on ME/CFS and several distinct biological changes have been discovered resulting in targeted interventions and thorough descriptions of the pathobiology of ME/CFS22,23. In opposition to the vast amount of biopathological evidence, the authors refer to a publication where the initial part of the summary reads: “The basic assumption underlying the model presented here is that the brain makes sense of the internal state of the body by being sensitive to statistical regularities in its own neural activity”24. the publication title seems to state the validity of this concept by “Taking the inferential leap” perhaps not knowing that inferring denotes either a conclusion based on known facts or the act of passing from statistical sample data to generalization. The authors fail to provide any of these.

Conclusion:
The “Oslo Declaration” epitomises the dangers of extrapolating findings from a small under-powered, narrowly focused study with data from unrelated studies (disorders) to explain a complex multi-factorial disease comprising different clinical subtypes that ME/CFS represents.
To quote the American literary critic HL Mencken:
“For every complex problem there is an answer that is clear, simple, and wrong.”

• Jesper Mehlsen MD , Klinik Mehlsen, Copenhagen, Denmark


• David Andersson, Professor of Neuroscience, King's College London, UK


• Professor Stuart Bevan, Professor of Pharmacology, King's College London, UK


• Professor Simon Carding, Head, Food, Microbiome, and Health Research Programme, Quadram Institute Bioscience, Norwich, UK


• Bernard Jeune MD, Lecturer emeritus, Department of Public Health, Syd Dansk University, Denmark


• Per Julin PhD MD, Department of Neurobiology, Karolinksa Institutet, Sweden


• Peter la Cour, Ph.D., professor, aut. Sundhedspsykolog,Klinik Mehlsen, Copenhagen, Denmark


• Professor emeritus Ola Didrik Saugstad MD, PhD, FRCPE, Oslo University Hospital, Norway


• Prof. Dr. Lutz Schomburg, Charité – Universitätsmedizin Berlin, Berlin, Germany

on behalf of

• Professor James N Baraniuk MD Department of Medicine, Georgetown University, Washington DC, USA


• Professor Jonas Bergquist, Inspector Equitandi, Uppsala University, Sweden


• Dr Amolak Bansal, Consultant Clinical Immunologist, Spire Healthcare, UK


• Beata Dela-Jaworska MD, East Coast Coummunity Healthcare, Norfolk, UK


• Anders Rosén, Professor Emeritus, Department of Biomedical and Clinical Sciences, Linköping, Sweden


• Associate Professor Sture Eriksson, Umeå University, Vice chairman, RME, Sweden


• Louise Gudbergsen MD,Doctor, Denmark


• Eva Maria Martin, Hospital de Manises Valencia, Valencia, Spain


• Associate Professor Rikke Olsen PhD, MSc, Department of Clinical Medicine –


• Research, Unit for Molecular Medicine, Aarhus University, Denmark


• Elisa Oltra PhD, Universidad Catolica de Valencia San Vicente Mártir, Valencia, Spain


• Markku Partinen MD PhD, Professor, Medical Director in Sleep Medicine, Department of Neurosciences, University of Helsinki, Finland


• PD Dr. Bhupesh Prusty, Group leader, Institute for Virology and Immunobiology, University of Wuerzburg, Germany


• Associate Professor Eva Untersmayr-Elsenhuber, MD, PhD Medical specialist in Immunology, Head of Gastrointestinal Immunology Research Group, Medical University of Vienna, Austria


• Kristin Sigurdardottir, Accident and emergency physician, Iceland


• Kristian Sommerfelt, Emeritus Professor, Department of Clinical Science, University of Bergen, Norway


• Marte Viken PhD, Project group leader, Senior researcher, Oslo University Hospital, Norway


• Lucinda Bateman MD, Bateman Horne Center, Utah, USA


• Wenzhong Xiao, Director of the Immuno-Metabolic Computational Center, Massachusetts General Hospital (MGH), Harvard Medical School, USA


• Nancy Klimas, MD, Director, Institute for Neuro Immune Medicine, Professor and Chair, Department of Clinical Immunology, Dr Kiran Patel College of Osteopathic Medicine, Nova Southeastern University, USA


• Executive Committee, European ME Alliance

---

References:

1. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, D.C: National Academies Press; 2015.
2. National Institute for Health and Care Excellence. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. 2021
3. Cairns R, Hotopf M. Occup Med (Lond). 2005 Jan;55(1):20-31.
4. Wilson A, et al. BMJ. 1994 Mar 19;308(6931):756-9.
5. Andersen MM, et al. J Psychosom Res. 2004 Feb 1;56(2):217–29.
6. Ghali A, et al. Diagnostics 2022, 12, 2540.
7. Carruthers BM, et al 2011 Oct;270(4):327-38.
8. Lien K, et al. Physiol Rep. 2019 Jun;7(11): e14138.
9. Joseph P, et al. Chest. 2021 Aug;160(2):642-651.
10. Booth NE, et al. Int J Clin Exp Med. 2012;5(3):208-20.
11. Tomas C, et al (2020) PLoS ONE 15(4): e0231136.
12. Hansen AL, et al. J Psychophysiol. 2013;27(2): 67–75
13. Rowe KS. Front Pediatr. 2019; 7: e00021.
14. Josev EK, et al. J Clin Med. 2021 Aug 16;10(16):3603.
15. Allen C, et al. Lancet. 1999;354(9186):1229–1233.
16. Arias D, Otto C. 2011 http://www.medirelax.com/v2/wp-content/uploads/2013/11/F.-Scope-of-Sensory-Deprivation-for-Long-Duration-Space-Missions.pdf.
17. Nakatomi Y et al.J Nucl Med 2014; 55:945–950 DOI: 10.2967/jnumed.113.131045
18. Mueller C, et al. Brain Imaging and Behavior 14, 562–572 (2020).
19. Tate W, et al. Front Neurol. 2022;13: 877772.
20. Goebel A, et al.: J Clin Invest. 2021;131(13):e144201.
21. Klein J, et al. Nature (2023). https://doi.org/10.1038/s41586-023-06651-y
22. Sotzny F, et al. Autoimmunity Reviews Volume 17, Issue 6, June 2018, Pages 601-609
23. Stanculescu D, Bergquist J. Front Med (Lausanne). 2022 Mar 8;9:818728.
24. Fedorowski, A., Sutton, R. Nat Rev Cardiol 20, 281–282 (2023).
25. Franke, C., Berlit, P. & Prüss, H. Neurol. Res. Pract. 4, 28 (2022).
26. Möller M, et al.. J Intern Med. 2023 Sep 27.