Advances in Understanding the Pathophysiologyof Chronic Fatigue Syndrome (Komaroff, 2019)

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JAMA. 2019 Jul 5. doi: 10.1001/jama.2019.8312. [Epub ahead of print]

Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome
Anthony L. Komaroff, MD
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

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 describedin the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many standard laboratory test results were normal, some clinicians ex-plained 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. Over the past 35 years, thousands of studies from laboratories in many countries have documented un-derlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong.

Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS “is 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.1

Over the past several years, the National Institutes of Health (NIH) has expanded its research efforts directed to-ward this disease. It has initiated an unusually comprehensive multisystem study at the NIH Clinical Center, funded 3 extramural ME/CFS research centers and 1 data coordinating center, awarded supplemental support to 7 existing grants, and held regular telebriefings on the illness (as has the Centers for Disease Control and Prevention).2

A 2-day conference at the NIH in April 2019 high-lighted recent progress. New research was presented that both reinforced and expanded on previous reports.Equally important, several plausible models were pro-posed that could explain many of the abnormalities thathave been described.

The Central and Autonomic Nervous System

Since the early 1990s, multiple studies have compared patients with ME/CFS with healthy age- and sex-matched controls and found abnormalities of the central and autonomic nervous system.3

•Neuroendocrine abnormalities were among the first evidence reported and involve impairment of several limbic-hypothalamic-pituitary axes (involving cortisol, prolactin, and growth hormone end products). Ageneral downregulation of the hypothalamic-pituitary-adrenal axis is seen in patients with ME/CFS, in contrast to the upregulation of the hypothalamic-pituitary-adrenal axis seen in major depression

Impaired cognition has been found by many investigators, including slowed information processing speed and impaired memory and attention that are not explained by concomitant psychiatric disorders.

•Magnetic resonance imaging has revealed increased numbers of punctate areas of high signal in white matter. Functional magnetic resonance imaging has demonstrated different responses to auditory and visual challenges and to tests of working memory, as well as altered connectivity between different brain regions.

•Positron emission tomography and magnetic resonance spectroscopy recently have demonstrated that patients with ME/CFS have a widespread state of neuroinflammation (particularly activation of microglialcells) as well as increased ratios of choline-creatinine and increased levels of lactate that correlate with levels of fatigue.4 Spinal fluid contains increased levels of proteins involved in tissue injury and repair.

•Autonomic nervous system abnormalities have been repeatedly demonstrated in ME/CFS, particularly altered systemic and cerebral hemodynamics that correlate with symptoms.5 At the NIH conference, it was reported that with prolonged upright posture, abnormal increases in heart rate and decreases in blood pressure are common; even when heart rate and blood pressure responses are normal, substantial cerebralblood flow reductions are noted.
continued here: https://jamanetwork.com/journals/jama/fullarticle/2737854
 
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Wishful

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I googled 'fatigue nucleus' and found another interesting article on "Neurobiological studies of fatigue": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479364/

It says: 'Common across these animal models is that fatigue arises when a stimulus induces activation of microglia and/or increased cytokines and chemokines in the brain.' That would fit my model for ME.

The paper does use CBT/GET as a proven treatment for CFS, so I wouldn't take the paper as a perfect understanding of fatigue. The idea of a specific part of the brain that controls our feeling of fatigue is interesting though, and I hope that gets more research, and that ME researchers look into that.
 
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"The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first describedin the mid-1980s."

Wait...What???
ME has been described since the 30s and in epidemics! What should be hushed up here all the time? Why does everyone ignore these statements? For decades, ME research has been blocked. And the invention of the "CFS" by the CDC was the worst of them all. just as bad as the IOM criteria 2015 and SEID. doesnt anyone understand? the IOM is not an independent company, but financed by eg insurance companies.

And why do doctors participate in this game? ME is NOT described since the 80s! Why?

Shame!
 
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Mary

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Here's an article by Cort, about the JAMA article linked above:
https://www.healthrising.org/blog/2...yndrome-article-tony-komaroff-unifying-model/

A couple of comments he makes:
Getting this article published in JAMA means more than quite a few doctors and medical students are getting a new view of ME/CFS. It also means the editorial staff of JAMA believes Komaroff’s message – that ME/CFS is a real disease – has merit and that doctors should be exposed to it – a good sign. Komaroff wrote:

JAMA’s “published very little about ME/CFS over the years, but are warming to the subject. They probably are the most widely read English language medical journal in the world, and so their interest is important. The implicit message of the article is that there is a complex underlying biology to ME/CFS and that health authorities are taking it very seriously—which will probably come as a surprise to many readers.”​
JAMA now knows that it has good reason to “warm” to ME/CFS. Komaroff’s article is not just beating the competition – it’s blowing it away. The 27,000 plus views it’s had over the past four days are far and away the most of any recently published article. Right now, Komaroff’s article is about 10,000 page views ahead of its closest competitor with most JAMA articles getting around 3-5K views.
So if you haven't checked the article out directly at JAMA, give it a look - the more views, the better!
https://jamanetwork.com/journals/jama/fullarticle/2737854
 

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just as bad as the IOM criteria 2015 and SEID
What objection do you have to the IOM report and SEID? They stated that PEM is a primary feature of ME/CFS and helps distinguish it from other illnesses, which I think is huge. The name SEID hasn't caught on of course, but at least they tried to incorporate the hallmark of ME/CFS into its name.
 
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What objection do you have to the IOM report and SEID? They stated that PEM is a primary feature of ME/CFS and helps distinguish it from other illnesses, which I think is huge. The name SEID hasn't caught on of course, but at least they tried to incorporate the hallmark of ME/CFS into its name.
The IOM criteria are very broad and there is a risk that patients who are actually suffering from another organic or even a primary psychiatric illness will be misdiagnosed. This definition does'nt require any exclusion diagnosis!

Remarkably, the fact that the disease starts with a viral infection in the vast majority of patients (around 80%) was not reflected in the diagnostic criteria, nor was the flu-like symptomatology, which typically flares up again and again in the course of the disease and accompanies each PENE.

Dr. Leonard Jason showed how the fukuda prevalence rate of 0.42% increases 2.8-fold with the new IOM criteria. Such a mix of patient populations is a disaster for research. except for those researchers who favor psychogenic causation.
 
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Dr. Leonard Jason showed how the fukuda prevalence rate of 0.42% increases 2.8-fold with the new IOM criteria. Such a mix of patient populations is a disaster for research. except for those researchers who favor psychogenic causation.
I was diagnosed in 5 minutes with SEID. After 55 years of no answer. Nothing was excluded, nothing else ruled out, no meaningful tests. I clearly meet these other criteria, but just don't push the issue.

But nobody will be studying me (too old) and I agree that we need to really clean up the study cohorts.

Meanwhile: what is it we wait for now?
 

Mary

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The IOM criteria are very broad and there is a risk that patients who are actually suffering from another organic or even a primary psychiatric illness will be misdiagnosed.
I disagree. Psychiatric patients don't get PEM. I don't know of any other illness which has PEM. As far as having no exclusion diagnosis, I think that's a good thing. I'm hypothyroid, many with ME/CFS have hashimoto's - I believe these would be considered exclusion diagnoses, just to name a couple of things. It seems someone with POTS would be ruled out as having ME/CFS because of an exclusion diagnosis.

FWIW, Jason Leonard does believe that the Canadian Consenus Criteria is stricter than Fukuda (https://me-pedia.org/wiki/Canadian_Consensus_Criteria) and Fukuda doesn't even require PEM as part of the diagnostic criteria. I don't think Fukuda has good or adequate diagnostic criteria.

This article does'nt help us if the historical view of ME is misrepresented. New researchers will not be aware of the past epidemics and will almost certainly be heading in the wrong direction.
I agree, the article did a very poor job of portraying the history of ME/CFS but I still think it's a good thing - apparently getting some respect at last! Maybe a few doctors will start believing their patients, maybe some researchers may get interested too. Maybe it will make it a little harder for the NIH to blow us off.
 
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I disagree. Psychiatric patients don't get PEM. I don't know of any other illness which has PEM.
No. PEM is not a unique criterion: Also, e.g. a proportion of multiple sclerosis patients experience PEM. However, the PENE in patients with ME is a symptom with a unique feature, because this term refers to the main symptoms after exertion that occur primarily in the neuroimmunological areas. And this phenomenon is probably not known by any other disease.
And btw "malaise" and "exhaustion" are two completely different terms. Malaise is downplaying, while exhaustion describes ME better. While PEM characterizes a purely subjective condition, PENE is an objectively measurable criterion and refers to the numerous profound dysfunctions in the neurological, immunological, cardiovascular and energy-producing systems of the body, which occur after only a minor strain and led to a long-lasting or even permanent disability.
In addition, fatigue is first on the list of symptoms in SEID and thus appears to the doctors as the main criterion.

As far as having no exclusion diagnosis, I think that's a good thing. I'm hypothyroid, many with ME/CFS have hashimoto's - I believe these would be considered exclusion diagnoses, just to name a couple of things. It seems someone with POTS would be ruled out as having ME/CFS because of an exclusion diagnosis.
That's not true, sorry.
ICC criteria:
"Exclusions: As in all diagnoses, exclusion of alternate explanatory diagnoses is achieved by the patient’s history, physical examination, and laboratory/biomarker testing as indicated. It is possible to have more than one disease but it is important that each one is identified and treated. Primary psychiatric disorders, somatoform disorder and substance abuse are excluded. Paediatric: ‘primary’ school phobia.

Comorbid entities: Fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve, migraines, allergies, multiple chemical sensitivities, Hashimoto's thyroiditis, Sicca syndrome, reactive depression. Migraine and irritable bowel syndromemay precede ME but then become associated with it. Fibromyalgia overlaps."

FWIW, Jason Leonard does believe that the Canadian Consenus Criteria is stricter than Fukuda (https://me-pedia.org/wiki/Canadian_Consensus_Criteria) and Fukuda doesn't even require PEM as part of the diagnostic criteria. I don't think Fukuda has good or adequate diagnostic criteria.
Yes, the CCC are stricter than fukuda. And the ICC are stricter than CCC. I did not say anything else.

I agree, the article did a very poor job of portraying the history of ME/CFS but I still think it's a good thing - apparently getting some respect at last! Maybe a few doctors will start believing their patients, maybe some researchers may get interested too. Maybe it will make it a little harder for the NIH to blow us off.
Unfortunately, then you have not understood my point, why it is incredibly important that the history is included in the research.
 
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"July 7, 2019
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..."


Comment below the article. So True! And so sad that komaroff either lies or does not know the ME history.
 

Wishful

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while exhaustion describes ME better.
I have to disagree with that. I wouldn't use 'exhaustion' or 'fatigue' to describe my ME. I'd say it's something interfering with normal function. Malaise is too vague to be useful, but I consider it a better fit for how I feel. I think 'sickness behaviour' is a better fit, but most people here seemed to like that even less.

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.
Actually, there is a disease named 'ME/CFS'. Google it, and you'll find plenty of references, including governmental sources. It may be a conflation of two other things that have had their definitions changed over time, but at present 'ME/CFS' and 'ME' are accepted as labels for a disorder that fits certain criteria.

A typical google hit:

"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), sometimes referred to as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS),"

It's just an aspect of the English language: vague, mutable, sometimes self-contradictory. We muddle along with it anyway. For now, 'ME/CFS' is recognized as a specific, if poorly defined, disease.
 
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No. PEM is not a unique criterion: Also, e.g. a proportion of multiple sclerosis patients experience PEM. However, the PENE in patients with ME is a symptom with a unique feature, because this term refers to the main symptoms after exertion that occur primarily in the neuroimmunological areas. And this phenomenon is probably not known by any other disease.
And btw "malaise" and "exhaustion" are two completely different terms. Malaise is downplaying, while exhaustion describes ME better. While PEM characterizes a purely subjective condition, PENE is an objectively measurable criterion and refers to the numerous profound dysfunctions in the neurological, immunological, cardiovascular and energy-producing systems of the body, which occur after only a minor strain and led to a long-lasting or even permanent disability.
In addition, fatigue is first on the list of symptoms in SEID and thus appears to the doctors as the main criterion.
I ever thought PENE is another try to grasp the same thing as PEM. I don´t see that there has achieved any groundbraking success in measering a condition that I would think to be the common thing in our illness. Interestingly the CCC come up with Post-Exertional-Fatique as an option beside of PEM (in point 2.).

So, what is it what we try to grasp? It won´t be just feeling worse after exertion, this happens in many many diseases.

My proposal were, that it carries the possibility to hit delayed -- no other disease will behave like that --, and that it carries the possibility to sidestep PEM/PEF/PENE by pacing -- no other disease will allow the patient not to feel bad when having done a certain amount of exertion (that only has been spent onto another area, say reading a book but not again playing chess, or going to the supermarket but not again working a bit in the garden).

ICC criteria:
"Exclusions: As in all diagnoses, exclusion of alternate explanatory diagnoses is achieved by the patient’s history, physical examination, and laboratory/biomarker testing as indicated. It is possible to have more than one disease but it is important that each one is identified and treated. Primary psychiatric disorders, somatoform disorder and substance abuse are excluded. Paediatric: ‘primary’ school phobia.

Comorbid entities: Fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve, migraines, allergies, multiple chemical sensitivities, Hashimoto's thyroiditis, Sicca syndrome, reactive depression. Migraine and irritable bowel syndromemay precede ME but then become associated with it. Fibromyalgia overlaps"
Probably we agree that there are different roads which can lead to mecfs. Other way around, mecfs might influence or even cause ill functioning in the body as well. I hope that researchers (and doctors, if possible) don´t loose their wit only because it´s difficult to spot the core of mecfs.

I think this point is rather of huge interesting, i.e. that PwME not only can display several comorbid entities, but also report many different vague and nonspecific symptoms and influences. What could be the reason? Hm it´s important, because ppl like to suggest it´s psychosomatic ...

I have to disagree with that. I wouldn't use 'exhaustion' or 'fatigue' to describe my ME. I'd say it's something interfering with normal function. Malaise is too vague to be useful, but I consider it a better fit for how I feel. I think 'sickness behaviour' is a better fit, but most people here seemed to like that even less.
I like to disagree with your disagree. When I was worse "exhaustion but not tiredness" described it rather very well. Now I am better, and the same thing but in much lesser amount takes place, and I wouldn´t describe it as feeling exhausted. So, was it a mistake to describe it like so when I was worse??

I think we should try to grasp some logic. I don´t thing that feeling exhausted would mean that there is less action per se in the body (in the brain which makes the feeling). I even think there might be more action, and only when tiredness comes up action would slow down, in the (ill) frame that has happened to be established in the brain. I think this relationship might be open for physiological interpretation.
 
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And again: PENE is a symptom with a unique feature, because this term refers to the main symptoms after exertion that occur primarily in the neuroimmunological areas.
PEM does not refer to these neuroimmunological symptoms after exertion. But that is an important criterion for ME.

It always amaze me how much the ICC criteria are resisted here. Maybe because then some would fall out of the grid? is it fear?
 
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And again: PENE is a symptom with a unique feature, because this term refers to the main symptoms after exertion that occur primarily in the neuroimmunological areas.
I agree btw that PENE is the best definition, but it´s new to me that it could be measured (with significance). This would be nice.

PENE
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are as follows:

1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
3. Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
4. Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.
The underlinend sequence is nothing else than an interpretation.

And they say furthermore that the symptoms would occure primarily in the neuroimmunological areas. This is reasonable - if you ask me - but it´s again only a try to spot the thing. Or are there reliable data? Would be new to me.