[Skip to Navigation]
Sign In
July 5, 2019

Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome

Author Affiliations
  • 1Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2019;322(6):499-500. doi:10.1001/jama.2019.8312

When does an illness become a disease? When the underlying biological abnormalities that cause the symptoms and signs of the illness are clarified.

The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many standard laboratory test results were normal, some clinicians explained to patients that “there is nothing wrong.” There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities.

Add or change institution
8 Comments for this article
Some observations...
Mark Pickin, MB ChB | Retired Physician
Very interesting but a few observations. As someone with panhypopituitarism I don't think that downregualtion of the hypothalamic-pituitary-adrenal axis is sufficient. Yes I've experienced great fatigue and sleepiness but nothing to the extent of ME/CFS and I could always carry on if necessary despite the fatigue and definitely did not have the post exertional effects. Maybe a component but not an underlying cause.

Secondly, I have encountered a small number of patients with ME/CFS who have experienced complete and immediate recovery with pain or severe illness.

The first was a 50 year old ex-ballerina who had had CFS
for about 10 years. She suffered a ruptured appendix with peritonitis and told me that immediately on coming round from the anaesthetic and despite her pain  she knew that her CFS had resolved... took her a few months to get back to full fitness, but she did.

Another was a girl of 16 who broke her arm, again with immediate recovery, and the third a consultant colleague who had a full thickness burn of the palm of her hand from a piece of hot metal.

These cases would very much support the idea of something going awry with the neuroencocrine system, offered as ideas for future research.
Coincidence ?
Daun Kauffman, M.Ed., MBA | School District Philadelphia
I can not help but observe significant overlap with symptoms of PTSD, especially chronic PTSD onset in childhood, with the later down-regulation cited and 'malaise' with PTSD dissociation, along with the general inflammation, immunological and other somatic expressions.
Rewriting History?
Guido den Broeder, drs. | GAME
There is no disease named 'ME/CFS'. The author conflates two diagnoses of a different type - one a disease, the other research criteria - that have little to do with each other.

Myalgic encephalomyelitis is a specific brain disorder with known enteroviral cause, hence its name and classification. The disease was previously coined missed or atypical poliomyelitis, until the definition of polio was changed in the 1950s to exclude nonparalytic cases. It has been researched for more than a century.

Chronic Fatigue Syndrome was invented in the 1980s by psychiatrist Straus behind the desk, just like SEID
by the IOM in 2015. The usefulness of such a heterogenous research diagnosis, not based on epidemiologic knowledge, is limited. Most of the money and effort thrown at it has been wasted. 'There is something medically wrong' is the best you will ever find. Worse: we stopped examining patients, in turn giving rise to treatments like CBT/GET.

Applying the term 'ME/CFS' obstructs scientific advancement and reduces the chance for all patients involved to receive proper treatment.
CONFLICT OF INTEREST: Chair of GAME (Global Advocates for Myalgic Encephalomyelitis)
Useful for Practitioners
Ketra Wooding | Patient/Consumer
I was delighted to have this article shared with me by my physiotherapist, who spotted it on twitter.

It's great to see that the latest (and fascinating) research into the pathomechanisms of ME/CFS is now easily discoverable by health practitioners.

Articles like this one will change the experience patients with ME/CFS have with their health practitioners, and improve their lives immeasurably.

Well done to all the researchers, whose work is represented here. Thank you.
Thank-You For a Great Article
Alllie Wallace, BScHons, Grad Dip Tch. | Patient and carer
It is wonderful to read an article detailing some of the great biomedical and physiological findings seen in people with ME/CFS . We have so many questions about this disease and its impact on our biochemistry and physiology, that remain unexplained, however it is great to read that objective bio-medical findings and abnormalities are being found, measured and quantified. I'm grateful that a journal the calibre of JAMA is tackling ME/CFS head on and that this journal has seen fit to publish such an informative article on ME/CFS.
Excellent Summary
Russell B | Patient & Support Facilitator
The is the most succinct overview I've read in a while and covers many important items of recent research and theory.

I've had CFS twice in my life, once 25 years ago and then a second time 5 years ago. Interestingly, both were markedly different but ticked all the boxes for defined CFS symptomology. The first episode I had in my early thirties, with the classic viral onset. I managed to overcome it completely within about 1.5-2 years. I was quite fit before and after. The more recent episode has proven quite complex and multi-layered and difficult to shake,
perhaps as it started in my mid-fifties when my body can't restore and repair like it used to. I'm much better now but just can't shake the last of it and can no longer work full time.

I've been running a chronic health support group for the last 3-4 years and studied the subject extensively, as well as psychology, pain and trauma (casually while couch-ridden). One thing that surprised me from running my group is there are traits which seem to be over-represented in chronic illness sufferers, including the ME/CFS/FM cohort, such as exposure to trauma (childhood or sudden adult or both) in some, social timidity, perfectionism in many, OCD etc. I joke that I've yet to meet a bunch of extroverts with ME/CFS. My theory is life experiences and genetics creates the fertile ground for whatever this illness is. I also agree with Daun Kauffman's observations above re trauma and Mark Pickin's remarks on recovery and the suspicion of involvement of the neuroencocrine system.

What I've been trying to put into words as to my theory of this illness is perfectly summarised in the sentence: "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?" I certainly believe this to be true in many cases, and it also offers hope that people can reduce the severity and duration of the illness through understanding and addressing these mechanisms. I also believe that the CNS/ANS may have difficulty differentiating true vs perceived threats and that the relentless stresses of modern life for some people (less resilient or more susceptible as summarised above) can be perceived as externally life threatening or internally invasive, eg by the immune system. I certainly felt that in both my episodes a single event triggered a domino effect of the symptoms I've experienced. So kudos to the author/s and the informed responses above.
Timely and Urgent
Galen Warden |
Just last week I took my 30-year-old son with severe CFS to the ER because he couldn't walk, had not slept for more than 2-hour spurts for 7 days, and was down below 110 pounds (at 5'10").

Because he had been living alone, and his CFS had recently become too severe for him to care for himself, he had completely languished and the last straw was triggered after an episode of vertigo a couple of weeks ago. I flew from my home state to get him to the ER and now I'm living with him as we try
to find a doctor able to provide diagnosis and treatment - which we haven't found yet.

Morristown Memorial Hospital kept him overnight for observation, told us all of his blood work looked normal, and referred him to a psychiatrist. We carried him back up the stair to his apartment where I am feeding and caring for him.

Please make this study widely available so that doctors no longer tell people like my son that it's in their head. Where can we go? Who can we see? I've been asking for an MRI because my instincts were saying it's so systemic, cellular, it must be controlled somehow neurologically. But what do I know? No doctor we've seen thus far is willing to explore, be curious, look at the research or help. Please reply with any suggestions for a caring physician who takes Medicaid, since my son has not been able to work for a few years now.

Signed - A mother willing to do anything to help her son
For those interested in ME/CFS
David Johnson, MD FAAFP | Allina Health
I would recommend the documentary Unrest (2017), viewable on Netflix. It's produced by, and features a Ph.D. student who develops the condition.