“It’s all in your head”: what long-COVID research has taught us about chronic fatigue syndrome
Article by Elizabeth Donald, BmedSci, MSc.
Among the spectrum of confounding SARS-CoV-2 (COVID-19) symptoms is the persistence of phenomena labelled long-COVID. Defined by a constellation of persistent long-term symptoms ranging from mild to debilitating including fatigue, depression, memory impairment and poor concentration, long-COVID has been compared to a condition known for decades: chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)1. Already a contentious and hotly debated issue among the medical community, tensions have now resurfaced around CFS/ME with the race to understand the origins of post-COVID sequelae.
CFS/ME is a complex long-term illness often triggered by an acute viral infection with a wide range of symptoms that can have a significant effect on daily activities, the most common being extreme fatigue1.
CFS/ME affects up to 250,000 people in the UK and an estimated 17 million worldwide, however up to 90% of sufferers remain undiagnosed2
The failure to identify a specific causative agent coupled with a lack of any abnormal, routine clinical laboratory test results has led many healthcare practitioners (HCPs) to conclude that CFS/ME lacks a pathophysiological basis and must therefore be of psychosomatic origin3.
Because of this lack of knowledge, many people suffering with CFS/ME have their symptoms dismissed as a psychological condition (ie ‘illness beliefs’), and are prescribed a combination of exercise, cognitive behavioural therapy and mindfulness, with limited success4-6.
...It is vastly easier to dismiss an illness as imaginary than to grapple with brain physiology.
This “all in your head” myth of CFS/ME has permeated medical discourse and popular culture, with destructive consequences for the millions of people living with the condition. In fact, patient surveys consistently report that people with CFS/ME encounter importunate medical scepticism, difficult interactions with HCPs and poor-quality care7. Forced to fend off accusations of laziness and hypochondria, people are left feeling vulnerable, alienated, and disillusioned with the healthcare profession.
As Jennifer Brea, a long-term sufferer of CFS/ME puts it, “Sickness doesn't terrify me and death doesn't terrify me. What terrifies me is that you can disappear because someone is telling the wrong story about you. I feel like this has happened to all of us living this.”
However, there is a silver lining. As a stream of novel research into chronic post-viral illness saturates the sphere of science and medicine, CFS/ME is gaining new respect. Long-COVID and CFS/ME are both considered post-viral syndromes with similar pathogenesis and patterns of neurological degeneration, secondary to viral infection.
They are the same disease — or very, very similar.
The latest research into the neurological effects of COVID-19 on the brain shows that there is a significant reduction in grey matter mass8, coupled with widespread neuroinflammation and evidence of oxidative stress9-12. One study found evidence that antibodies produced in response to COVID-19 may mistakenly target endothelial cells crucial to the blood-brain barrier, causing blood vessel thinning and leaks between the tight-junctions of cells13. Once leakage occurs, immune cells such as macrophages attempt to repair the damage and initiate inflammation pathways. Researchers from this study found that in areas were endothelial cells were damaged, 300 genes showed decreased expression, while genes associated with oxidative stress were increased. Numerous other studies have linked oxidative stress to the brain-fog and fatigue experienced by people with long-COVID9-12.
In a lab at La Trobe University in Australia, a team of researchers led by Dr Nick Reynolds have just linked the pathophysiology of long-COVID to neurodegenerative processes previously only observed in Alzheimer’s disease, with deposits of amyloid-like plaques identified in brain tissues14.
To cut a long story short, these amyloid plaques are very toxic to the brain cells, and we hypothesise that aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19 that many of us call brain fog.
If this is confirmed in future studies, Reynolds believes drugs developed to combat Alzheimer’s and Parkinson’s could be repurposed to revolutionise treatment for the debilitating neurological symptoms of long-COVID.
What is interesting about this novel long-COVID research is that it mirrors research that has been published about CFS/ME for years. For example, a similar pattern of grey and white matter loss has been observed in the brains of people with CFS/ME15,16, while neuroinflammation mediated by oxidative stress has also been well documented17-21. A recently published case study also found amyloid-like plaque build-up in a patient with CFS and notes that further investigations into the role of CNS disease in CFS/ME is warranted22.
The similarities between these two conditions are becoming undeniable, affording validation and hope to millions of people suffering from the debilitating symptoms of chronic fatigue and cognitive impairment. As scientists continue to decipher the parallels between long-COVID and CFS/ME, the findings have potential to help both groups of patients.
- Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci. 2022;16:888232.
- Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clin Proc. 2021;96(11):2861-2878.
- Friedman KJ, Murovska M, Pheby DFH, Zalewski P. Our Evolving Understanding of ME/CFS. Medicina (Kaunas). 2021;57(3).
- White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43(10):2227-2235.
- Komaroff AL. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Real Illness. Ann Intern Med. 2015;162(12):871-872.
- Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. 2008(3):CD001027.
- ME Association. 'ME/CFS Illness Management Survey Results: No decisions about me without me'. https://meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf. Accessed 8 August 2022.
- Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604(7907):697-707.
- Skesters A, Kustovs D, Lece A, Moreino E, Petrosina E, Rainsford KD. Selenium, selenoprotein P, and oxidative stress levels in SARS-CoV-2 patients during illness and recovery. Inflammopharmacology. 2022;30(2):499-503.
- De la Cruz-Enriquez J, Rojas-Morales E, Ruiz-Garcia MG, Tobon-Velasco JC, Jimenez-Ortega JC. SARS-CoV-2 induces mitochondrial dysfunction and cell death by oxidative stress/inflammation in leukocytes of COVID-19 patients. Free Radic Res. 2021;55(9-10):982-995.
- Chiricosta L, Gugliandolo A, Mazzon E. SARS-CoV-2 Exacerbates Beta-Amyloid Neurotoxicity, Inflammation and Oxidative Stress in Alzheimer's Disease Patients. Int J Mol Sci. 2021;22(24).
- Vollbracht C, Kraft K. Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C. Front Pharmacol. 2022;13:899198.
- Lee MH, Perl DP, Steiner J, Pasternack N, Li W, Maric D, et al. Neurovascular injury with complement activation and inflammation in COVID-19. Brain. 2022;145(7):2555-2568.
- Charnley M, Islam S, Bindra GK, Engwirda J, Ratcliffe J, Zhou J, et al. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19. Nat Commun. 2022;13(1):3387.
- Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, et al. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol. 2012;85(1015):e270-273.
- Finkelmeyer A, He J, Maclachlan L, Watson S, Gallagher P, Newton JL, et al. Grey and white matter differences in Chronic Fatigue Syndrome - A voxel-based morphometry study. Neuroimage Clin. 2018;17:24-30.
- Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014;12(2):168-185.
- Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2017;54(9):6806-6819.
- Maes M, Leunis JC. Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett. 2014;35(7):577-585.
- Maes M, Bosmans E, Kubera M. Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers. Neuro Endocrinol Lett. 2015;36(5):439-446.
- Maes M. A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by neuro-immune biomarkers. Neuro Endocrinol Lett. 2015;36(4):320-329.
- Ferrero K, Silver M, Cocchetto A, Masliah E, Langford D. CNS findings in chronic fatigue syndrome and a neuropathological case report. J Investig Med. 2017;65(6):974-983.