I knew humans could resemble worms, but this?

My wife and I are entering an age where our aches and pains are becoming a major ongoing topic of conversations. The pain of raising kids has transitioned into the pains of growing older. These aches and pains are, in the scheme of things, minor and intermittent.

At work I get to see real suffering and it keeps my own in perspective. And there are a lot of people who feel awful, some for obvious reasons such as cancer or AIDS, and some from ailments that are more enigmatic, such as systemic exertion intolerance disease (SEID), the illness formerly known as chronic fatigue syndrome.

Worst. Gateway disease. Ever.

In the context of SBM, SEID is a gateway disease into the world of pseudo-medicine.

A syndrome with no known cause and few effective therapies at best, those who suffer from it are easy pickings for SCAM practitioners. When you feel like crap month after month with no improvement or even an explanation for your suffering, you keep looking until you find an answer.

For example, those with ‘chronic Lyme disease‘ have the same phenotype as SEID patients:

A subset of patients reporting a diagnosis of Lyme disease can be described as having alternatively diagnosed chronic Lyme syndrome (ADCLS), in which diagnosis is based on laboratory results from a nonreference Lyme specialty laboratory using in-house criteria. Patients with ADCLS report symptoms similar to those reported by patients with chronic fatigue syndrome (CFS)…In British Columbia, a setting with low Lyme disease incidence, ADCLS patients have a similar phenotype to that of CFS patients.

These patients have the misfortune of being sucked into the chronic Lyme vortex when they probably have SEID, whatever that is. And there are other pseudo-diseases that have been misidentified as the etiology of SEID.

There has always been the question as to whether SEID is due to an infectious disease. One of the patterns I have noted over the years is the high functioning people who develop an acute illness and never, or slowly, recover. In a subset of patients SEID sure seems to me to be some sort of acute to chronic infection, or at least triggered by an infection.

While there is certainly another subset of patients whose underlying process is depression, they are different from SEID patients who have an acute onset of symptoms, a remarkable need to sleep, and the ‘brain fog’.

SEID sure looks like an infection. There are even outbreaks. But from what organism? Over the years a there have been a variety of infectious agents purported to cause SEID. When I was an intern at the end of the last century it was EBV. Others have suggested less legitimate causes such as Candida, promoted by Dr. Crook in his book The Yeast Connection. The snark makes itself. I was quite excited a few years back over the discovery of XMRV as a potential cause of SEID and was disappointed it did not pan out. But despite extensive investigations, no one infection has been implicated as a cause or coinfection with SEID.

Lots of panning, little gold

Perhaps SEID is some sort of post-infectious/post-inflammatory process, but that never panned out either. Immunologic? Maybe. But that idea has had little traction as well.

I found it intriguing that CFS patients appear to have different expression of genes (and here) but that never panned out either. Many of these studies suggest that SEID sufferers are physiologically different than those without the syndrome, but a unifying etiology remained elusive.

Seeing patients with this process is rarely satisfying. I don’t know what you have, I don’t know why you have it, I have nothing to offer you, and I do not know when, or even if, you will get better.

I don’t use those words of course, but that is the basic message. I always thought that SEID was post-infectious immunologic/inflammatory process like rheumatic fever that one day someone would figure out. In the meantime I have used the metaphor with patients of a rock thrown into a pond. The rock, whatever it was and in my speculations assumed to be an illness, started with a splash. The rock is gone, and now the patients are left with the ripples of SEID, slowing fading. I thought it was a good metaphor, but who knows.

Now there is a new study, “Metabolic features of chronic fatigue syndrome“, that suggests an entirely different pathophysiology:

Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline–5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism.

When compared to controls, SEID metabolism is slowed down, and most resembles, of all things, the dauer state of a nematode.

Dauer, which means persistence or long-lived in German, is an example of one well-studied system. The developmental stage of dauer is a hypometabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical features. Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes that are triggered by exposure to adverse environmental conditions. Entry into dauer confers a survival advantage in harsh conditions.

The dauer state is one of many hypometabolic states including:

diapause, hibernation, estivation, torpor, ischemic preconditioning, ER stress, the unfolded protein response, autophagy, and caloric restriction.

The hypothesis certainly fits what is seen clinically and it would be nice to have a final common pathway to explain a syndrome that appears after a variety of insults.

The results are preliminary, with a small number of people, and needs replication. So maybe it will pan out or just be another dead end. But it would a very satisfying explanation of SEID if validated.

Ooh, it makes me wonder…

And it also makes me wonder why. Humans don’t hibernate (medical conferences not withstanding), but we certainly have an evolutionary history filled with harsh conditions. Is SEID some sort of some sort of pathologic residue from what was once a beneficial response to stress in our Fred and Barney past, like depression (and given the profound motor retardation of depression, is depression a variation on a dauer theme?) or is the metabolic syndrome a residual from our tuberculous past? Who knows. But fun to think about.

And I wonder how long before naturopaths offer anti-dauer therapy? If nothing else, 200C C. elegans should be the homeopathic treatment.


Posted by Mark Crislip

Mark Crislip, MD has been a practicing Infectious Disease specialist in Portland, Oregon, since 1990. He is a founder and  the President of the Society for Science-Based Medicine where he blogs under the name sbmsdictator. He has been voted a US News and World Report best US doctor, best ID doctor in Portland Magazine multiple times, has multiple teaching awards and, most importantly,  the ‘Attending Most Likely To Tell It Like It Is’ by the medical residents at his hospital. His growing multi-media empire can be found at