Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: when suffering is multiplied, by Anthony L Komaroff in Healthcare 2021, 9(7), 919 [] 20 July 2021 (This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)


Article abstract:

Prof Anthony Komaroff

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness defined predominantly by symptoms. Routine laboratory test results often are normal, raising the question of whether there are any underlying objective abnormalities.

In the past 20 years, however, new research technologies have uncovered a series of biological abnormalities in people with ME/CFS. Unfortunately, many physicians remain unaware of this, and some tell patients that “there is nothing wrong” with them. This skepticism delegitimizes, and thereby multiplies, the patients’ suffering.


A large literature now describes multiple underlying biological abnormalities in people with ME/CFS. Some of the evidence comes from tests that have been available for decades but are not part of the “standard” laboratory test battery [4], and some evidence comes from the new technologies mentioned above. Unfortunately, many physicians are unaware of the new discoveries about ME/CFS.

The abnormalities all converge on and can affect the brain, and fall into five categories.

  • First, there are anatomic, physiologic and electrical abnormalities in the brain [5].
  • Second, various elements of the immune system are chronically activated and in some people those elements are exhausted—perhaps secondary to years of chronic activation [5]. This includes chronic activation of the brain’s innate immune system—neuroinflammation [6]. It also includes evidence of autoimmunity, including autoantibodies directed at targets in the central and autonomic nervous system [7].
  • Third, there also is evidence of impaired energy metabolism: the person with ME/CFS feels he or she lacks “energy” because his or her cells have a reduced ability to generate energy molecules (adenosine triphosphate, or ATP) [8]. Along with the abnormalities in energy metabolism, there is associated oxidative stress, or redox imbalance [8].
  • Fourth, the autonomic nervous system is dysregulated, one consequence of which appears to be impaired blood flow to the brain [9].
  • Fifth, there are characteristic abnormalities of the gut microbiome [10], with increased numbers of pro-inflammatory bacterial species and decreased numbers of butyrate-producing anti-inflammatory species.

What remains unclear are the mechanistic details as to how the abnormalities in each of these five categories affect each other, and whether one of them is the initial and primary abnormality [5,8]. In this next decade, the growing community of global investigators who are studying ME/CFS should place a high priority on refining our understanding of each of these categories of abnormality, and an even higher priority on understanding how they are connected. This is essential for developing good diagnostic tests, and effective treatments.

Whitney Dafoe ends the description of his suffering by emphasizing the silver lining around the cloud that he has lived with for nearly 20 years. He says he has learned a great deal about what is important in life, and that “ME/CFS is the greatest teacher I’ve ever had.”

I would like to think that ME/CFS will also prove to be a great teacher to the growing community of physicians and biomedical investigators involved in caring for and studying the illness. In particular, I speculate that the connections between the various abnormalities involving the central and autonomic nervous system, immune system, energy metabolism, redox imbalance, and the human microbiome that have been noted in ME/CFS will prove to be central also to the pathophysiology of many other diseases.

In particular, the COVID-19 pandemic appears to be producing millions of new cases of an ME/CFS-like condition [11], and NIH has allocated more than $1 billion to study this and other post-COVID chronic illnesses. Hopefully, this investment will produce more answers.

Of the personal lessons that I, as a physician, have learned from ME/CFS, perhaps the most important is that, if patients tell you they are suffering, your default assumption should be to believe them—even if you cannot find an answer with the diagnostic technology you first deploy. Above all, never succumb to the temptation to dismiss the patient’s symptoms because you cannot explain them. That may ease your anxiety, but it only multiplies the patient’s suffering.

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