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NIH Conference Review of Chronic Fatigue Syndrome

The current issue of JAMA reviews recent advances on chronic fatigue syndrome, also known as myalgic encephalomyelitis/(ME/CFS), based on a 2-day conference held at the NIH in an April 2019.

The syndrome was first described in the mid-1980s, with little known about its underlying biology and confusion about why patients who were so affected had normal laboratory tests and investigative findings.  

In 2015, the Institute of Medicine concluded that ME/CFS “ a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,” affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually.

The NIH 2-day conference reviewed recent progress and new research in several areas described below.

The Central and Autonomic Nervous System

Research in the last 30 years has shown that ME/CFS have abnormalities of the central and autonomic nervous system compared with matched controls.  This includes:

  • Neuroendocrine abnormalities, impairment of several limbic-hypothalamic-pituitary axes and downregulation of the hypothalamic-pituitary-adrenal axis.
  • Impaired cognition, memory and attention.
  • Abnormal positron emission tomography and magnetic resonance spectroscopy showing evidence of neuroinflammation (particularly activation of microglial cells).
  • Autonomic abnormalities. 

Metabolic Changes

Metabolomics have revealed several abnormalities in patients with ME/CFS, including evidence of oxidative stress and nitrosative stress. 

Immunologic Changes

The most consistently reported immunologic findings are increased numbers of activated cytotoxic CD8+ T cells and poorly functioning natural killer cells. Some studies have shown elevated cytokines in patients with ME/CFS, especially in the first 3 years of illness.  


What if ME/CFS reflects the activation of biologically ancient, evolutionarily conserved responses to injury or potential injury, a pathological inability to turn these responses off, or both? Several presentations at the NIH conference, citing work in animal models, indicated that low-grade neuroinflammation triggers protective behavioral changes, including reduced activity and appetite and increased sleep; this helps to focus the available energy on preventing or healing the injury. This stereotyped behavior change is likely triggered by a “fatigue nucleus” (a group of neurons); the nucleus is triggered, in turn, by the cytokines produced by neuroinflammation.

The neuroinflammation could have different triggers in different individuals. In some, it could be induced by brain infection (such as by chronic herpesvirus infection), autoantibodies, neurotoxins, or chronic stress; or alternatively systemic inflammation (e.g., gut inflammation) may lead to the brain being affected. 

It is possible that the hypometabolic state seen in patients with ME/CFS might also reflect a second and possibly related biologically ancient response to injury.


ME/CFS research remain a challenge, and research has not yet yielded the insights or approaches to better guide treatment. Currently there are no US Food and Drug Administration–approved treatments.  Despite the numerous abnormalities resported with ME/CFS patients, none yet have demonstrated the high sensitivity and specificity necessary to be diagnosticaly or therapeutically useful. 

More research is needed to understand the pathophysiology of ME/CFS and how to best treat it.


The author has no conflicts of interest to disclose related to this subject

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