Chronic Fatigue Syndrome – recognizing and treating an elusive highly debilitating condition

Dr Elisabetta Burchi, MD, MBA
Clinical Psychiatrist
Translational Research Lead at Parasym.
The epidemiological impact of Long Covid has prompted renewed attention towards one of the most debilitating, but also elusive, clinical pictures – the so-called “chronic fatigue syndrome” (CFS). As shown by perspective and retrospective studies, a significant percentage of Covid-19 patients, well after the resolution of the acute infection, continue to experience persistent debilitating fatigue, along with cognitive impairment (often referred as "brain fog"), orthostatic intolerance (namely an intolerance to the upright position), myalgias (i.e.  diffuse muscle pain), and disrupted sleep. All these symptoms, grouped under the umbrella of “Long Covid”, may meet criteria for CFS. For this reason, the last two years have re-initiated a more overt conversation about CFS and its potential treatments.
 With “chronic fatigue syndrome/CFS” we refer to a multisystemic condition mainly characterized by chronic unexplained and unrelievable fatigue that results in substantial reduction in pre-illness levels of mental and physical activity. CFS is often a misunderstood and misdiagnosed syndrome, potentially due to the nonspecificity of each symptom taken separately and the lack of analytical biomarkers. Confusion about this syndrome also started with its denomination.

 This non-specific name, “CFS”, was adopted by the centers of disease control and prevention in 1988 to substitute a previous denomination, “myalgic encephalomyelitis” (ME), that appeared in the literature in 1956 to describe a series of perplexing outbreaks characterized by consistent symptoms – such as severe muscle pain, low and persistent fever, headache, peripheral nerve disturbances, behavioral changes - that had been observed over the preceding few decades in various locations throughout the world and attributed to local and non-conforming denominations (ie. Da Costa syndrome, neurasthenia Iceland disease, Royal free disease, Epidemic Neuromyasthenia). The new name, CFS, aimed to be more reflective of the phenotype, but also to drop any reference to the etiology, which increasingly appeared to be unambiguously vague.

As a landmark report published by the US Institute of Medicine (IOM) in 2015 suggested, neither of the terms of the dyad (ME/CFS) that has been used to label the syndrome in the last 30 years,  may be appropriate: the first being misleading in relation to the pathogenesis; the second being so clinically vague to lead to trivialization and neglect of the condition. In order to address these issues, the IOM suggested renaming the syndrome as “systemic exertion intolerance disease” (SEID), to better reflect the multisystemic pathogenesis and the central feature of the syndrome.

Indeed, post-exertional malaise (PEM), defined as the exacerbation of the individual’s set of symptoms after previously tolerated physical, cognitive, orthostatic, emotional, or sensory efforts, is the distinct hallmark of CFS. PEM can be distinguished from the post-exertional fatigue experienced in other fatiguing illnesses or in deconditioning by the unique feature that sees a worsening in generating energy on a repeated test.

According to the latest diagnostic criteria proposed by the IOM , post-exertional malaise must be present at least 50% of the time during a 6-month period accompanied by substantial impairment compared to pre-illness functioning, and unrefreshing sleep, along with either cognitive impairment or orthostatic intolerance for SEID to be formally diagnosed.

Based on these criteria, with an average onset in the mid-thirties, SEID -  or CFS as it is still referred to in the medical community and as, for simplicity,  we will continue to adopt in the paper -  is estimated to affect up to 1% of the population worldwide, with approximately one-in-four patients that are house-bound. 


While the exact etiology and the specific biomarkers of CFS are still uncertain, there is now ample evidence for complex objective immunologic, autonomic, neurological, and energy metabolism impairments associated with this syndrome: 

  • CFS often follows an infectious illness and autoantibodies (ie. anomalous antibodies directed against the individual’s own tissues) are found in around 60% of individuals with the syndrome; other immunological features can be present, such as impairment of NK cells, that seems to make patients more vulnerable to infections;
  • Orthostatic intolerance (Oi) is recognized in up to 95% of the individuals affected by CFS and includes orthostatic hypotension, postural orthostatic tachycardia syndrome, and neurally mediated hypotension; OI has therein been associated to a series of imbalances of the autonomic system, such as decreased nocturnal parasympathetic/sympathetic activity ratio and reduced heart rate variability, which in turn have also been associated with unrefreshing sleep, another symptomatic feature of this syndrome;
  • Brain studies in these individuals have reported neuroinflammation, reductions in white matter, and decreased cerebral blood flow; these findings are associated with multiple cognitive deficits, such as decreased information processing speed which is the most commonly found in this population;
  • The presence of abnormalities in cellular bioenergetic, particularly in the generation of adenosine triphosphate (ATP), the main energy molecule, have been found and associated with PEM.


Although there are no specifically approved treatments for CFS, clinicians can recur to standard pharmacologic and nonpharmacologic treatments to address individual presenting symptoms. PEM could be treated with pacing of physical and cognitive activity, while OI could be treated with salt and fluid loading, fludrocortisone, low-dose beta blockers, alpha-adrenergic agonists and vagal stimulation. 

Notably, vagal nerve stimulation is particularly promising in the treatment of CFS not only because of the impact on OI, but also for pain and insomnia management, its anti-inflammatory effect, and its cognitive impact. In fact, vagal nerve stimulation has already been shown to improve heart rate variability and to correlate with multiple health benefits across both Long Covid and CFS. In particular, non-invasive neuromodulation targeting the vagus nerve through the Nurosym device, has already shown to increase heart rate variability, to reduce inflammatory cytokines, as well as to improve mood and energy levels, in patients with Long Covid and long term fatigue.

These therapeutic effects corroborate the immuno-neural pathophysiological hypothesis that sees the disruption in the anti-inflammatory effect of the vagus nerve and in the overactivation of the sympathetic activity as one of the mechanisms underpinning ME/CFS. 



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