How ME/CFS Progresses: A Framework for Research and the Prevention, Treatment, and Rehabilitation in ME/CFS Nacul et al 2019

John Mac

John Mac

Senior Member (Voting Rights)
Abstract
We propose a framework for the understanding of the pathophysiology and management of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease.

As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease.

Disease incidence depends on genetic makeup and environment factors, the exposure to an insult, or repeated insults, and the nature of the host response.

In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states.

Thus, the predominantly neuro-immune and autonomic manifestations, underlined by a hyper-metabolic state, that characterise early disease, may be followed by various processes leading to multi-systemic related symptoms.

This abnormal metabolic state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production.

These processes do not seem to happen uniformly; although a spiralling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium.

Disease management and research efforts should seek to identify and apply strategies targeted at the different pathophysiological dysfunctions that characterise different disease stages.

As disease presentation varies over time, no single case description, set of diagnostic criteria, or molecular feature is currently diagnostic for all patients at all times.

While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may improve research design and health care interventions for people with ME/CFS.
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https://www.preprints.org/manuscript/201909.0188/v1
 
John Mac said:
Thus, the predominantly neuro-immune and autonomic manifestations, underlined by a hyper-metabolic state, that characterise early disease, may be followed by various processes leading to multi-systemic related symptoms.
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Neuro-immune would mean related to the brain's immune system. Neuro-immune as used in the ME/CFS community seems to be a buzzword with little substance behind it.

We also have no idea how the metabolism changes over time, or whether the currently in some instances contradictory metabolic findings are contradictory because patients are being examined at different stages of an illness that progresses from one metabolic state to a different one. It could also be that these differences are due to sample processing and testing methods or due to the existence of subgroups.

However I would agree that my illness seems to change and evolve over time.

Disease management and research efforts should seek to identify and apply strategies targeted at the different pathophysiological dysfunctions that characterise different disease stages.
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That seems to be a sensible approach.
 
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The PDF of the article is open access. It's 16 pages of detailed biomedical information and hypotheses that I don't have the brain to read today but looks interesting. The point that ME seems to change over time and go through different biomedical stages is interesting, and their longitudinal study seems a very good idea. A pity that, by definition, it will take a long time.
 
This might be a very worthy document and like @Trish I simply don’t have the brain power to read a long very dense document at present so I skipped to the severe sections. Whilst I agree with idea of the illness advancing and compounding with cumulative effects of abnormalities I did notice the word rehabilitation cropping up a lot???

I also saw this
“Looking at other models of disease that include ‘invisible stages’ of illness brings us to the change in focus that evolved in the study of Alzheimer’s disease. Over the past decade, a conceptual shift to consider the disease as a continuum has occurred and, along with the discovery of biomarkers, has re-focused the research agenda towards the pre-clinical stage and early intervention (Dubois et al., 2016)Similarly, we suggest that a re-focus of the ME/CFS research agenda towards the pre-clinical stage by way of larger cohort studies, may contribute to revealing potential risk factors to support primary prevention efforts.”

Which frankly gives me the shivers because I feel like an end stage Alzheimer’s or MS patient might feel ie oh dear you’re too screwed to do anything with let’s focus on prevention instead. I’ve no problem with a general broad increased research effort but the word refocus if it means redirection to the easier option of preventative care would to me in context of tiNY existing biomedical research effort be unfortunate

Edit i also think nihr & uk generally would Lap up early intervention possibly behavioral versus biomedical research of more serious cases research
 
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The evolves through stages theory of ME is not new, but thank you to the authors for looking at this.

Although how to prevent ME seems to me impossible, given the number of "insults" out there: chemicals, toxic metals, viruses, bacteria, surgeries, accidents etc.


My own experience indicates to me at least, there are stages. However, this might just be n=1.

Early on I read Katrina Berne's Running on Empty: The Complete Guide to Chronic Fatigue Syndrome (CFIDS).

In her book, Dr. Berne talks about the progression to cognitive dysfunction following physical dysfunction.

That was partly how it was in my case: first significant physical problems, then added in cognitive problems.

However, problems with short term memory started quite early on before the brain fog/confusion, dizziness, problems with speech, headaches, etc. became issues.

Here is the MEpedia site about Dr. Berne, and her work:

https://me-pedia.org/wiki/Katrina_Berne

ETA:

Pre-clinical - scientists may want to look at pwIBS. There may be some potential there, as many with ME had IBS prior to ME.
 
DokaGirl said:
The evolves through stages theory of ME is not new, but thank you to the authors for looking at this.

Although how to prevent ME seems to me impossible, given the number of "insults" out there: chemicals, toxic metals, viruses, bacteria, surgeries, accidents etc.


My own experience indicates to me at least, there are stages. However, this might just be n=1.

Early on I read Katrina Berne's Running on Empty: The Complete Guide to Chronic Fatigue Syndrome (CFIDS).

In her book, Dr. Berne talks about the progression to cognitive dysfunction following physical dysfunction.

That was partly how it was in my case: first significant physical problems, then added in cognitive problems.

However, problems with short term memory started quite early on before the brain fog/confusion, dizziness, problems with speech, headaches, etc. became issues.

Here is the MEpedia site about Dr. Berne, and her work:

https://me-pedia.org/wiki/Katrina_Berne

ETA:

Pre-clinical - scientists may want to look at pwIBS. There may be some potential there, as many with ME had IBS prior to ME.
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I also had physical symptoms before any cognitive symptoms. And IBS many years before that.
 
I thought I had IBS, symptoms were similar anyway. But then (long story) found in fact I had diverticulosis.

Was diagnosed with diverticulitis on a trip to visit daughter in London, and the nature of the pain I had then was exactly what I'd felt before when I thought IBS was playing up. So best to try get this checked out - diverticulitis can be serious, I'm very grateful to St Thomas's Hospital for diagnosing and treating me.
 
Prevention might well of course involve avoidance of "pushing through" possible very early symptoms, the significance of which may not be understood. As yet we do not know if the observed onset is when someone's ME really starts, or if it is simply a "final straw" threshold that is finally breached, after what might have been months or years of some unrecognised developing physiological change. If the latter, and if the unrecognised changes could be detected earlier on, then it might just be that careful energy management could prevent the final straw stage being reached. All conjecture on my part of course.
 
Barry said:
Prevention might well of course involve avoidance of "pushing through" possible very early symptoms, the significance of which may not be understood. As yet we do not know if the observed onset is when someone's ME really starts, or if it is simply a "final straw" threshold that is finally breached, after what might have been months or years of some unrecognised developing physiological change. If the latter, and if the unrecognised changes could be detected earlier on, then it might just be that careful energy management could prevent the final straw stage being reached. All conjecture on my part of course.
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But not possible if you have caring or parenting demands (for example). Additionally, the 'final straw' may be an acute infection or other disease, an accident etc.
 
Barry said:
Prevention might well of course involve avoidance of "pushing through" possible very early symptoms, the significance of which may not be understood. As yet we do not know if the observed onset is when someone's ME really starts, or if it is simply a "final straw" threshold that is finally breached, after what might have been months or years of some unrecognised developing physiological change. If the latter, and if the unrecognised changes could be detected earlier on, then it might just be that careful energy management could prevent the final straw stage being reached. All conjecture on my part of course.
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As gradual onset likely at least 8 years undiagnosed this is definitely a needle/needles in a haystack situation trying to identify what actually contributed and what was completely irrelevant. You don’t pick up the drip drip worsening as anything remarkable until it has stacked up into something big enough to register as not normal. How you would pick up on it sooner would take a change of thinking from medics and public awareness i don’t see how that would work without some kind of test that could be carried out on people who have flu type illness symptoms to say oh you haven’t got flu you’ve got mild ME.
 
NelliePledge said:
As gradual onset likely at least 8 years undiagnosed this is definitely a needle/needles in a haystack situation trying to identify what actually contributed and what was completely irrelevant. You don’t pick up the drip drip worsening as anything remarkable until it has stacked up into something big enough to register as not normal. How you would pick up on it sooner would take a change of thinking from medics and public awareness i don’t see how that would work without some kind of test that could be carried out on people who have flu type illness symptoms to say oh you haven’t got flu you’ve got mild ME.
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Onset of diabetes, as I understand it, is a tipping point following physiological changes that may have been developing for years. Once upon a time those pre-onset changes were not understood, but now they are, and are detectable.
 
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Barry said:
Onset of diabetes, as I understand it, is a tipping point following physiological changes that may have been developing on for years. Once upon a time those pre-onset changes were not understood, but now they are, and are detectable.
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Wearables will come into their own for this. Chemistry of anode/ cathode tweakable to be sensitive to different compounds. There is a plethora of PhD students doing such projects.

Kraft assay test picks up pre diabetes stage, devised decades ago but not used clinically.
 
Cinders66 said:
Whilst I agree with idea of the illness advancing and compounding with cumulative effects of abnormalities I did notice the word rehabilitation cropping up a lot???
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Yes, I noticed that, too. They don't actually say anything 'wrong' about rehabilitation. Their definition of rehabilitation is broad, e.g. gentle physio to improve range of motion counts just as much as rehab as a gradual return to work. And they intend rehab to be adapted based on the stage the patient is at, e.g. an already recovering patient can carefully increase activity, a deteriorating one cannot. Unfortunately the sheer number of times the word rehabilitation is used is highly likely to cause a non-expert reader to conclude that most ME patients can be rehabilitated to health. If only!

Too much emphasis on fatigue, again. Compare to other fatiguing illnesses, study fatigued patients after acute illness to see who goes on to develop ME, etc. For the 517th time: think fatiguability, not fatigue!!!

But a lot of good in there, too.

I like the suggestion of making an early, provisional diagnosis and telling patients to rest and pace already then. It may just help them recover or at least to not deteriorate as much.

Many good suggestions, too, for improving ME research in the future, from the types of studies needed to patient selection criteria and stratification. Sadly no mention of where to get the money from to do it all (not the authors' fault I hasten to add).
 
The paper refers to a presentation given by Schweitzer in 1998 about phases in ME. Not sure we've made any progress in further investigating the observations made back then.
  1. Study, recognize, and name the types of the disease. Those who have lived with and worked with chronic fatigue syndrome know that, like Multiple Sclerosis, it presents itself in different forms. We would like these recognized with diagnostic criteria and official nomenclature.
  • Prodrome, or the period of slow onset prior to the tell-tale collapse. This is critical to disease prevention and should be a Level One Priority of the federal government through the Centers for Disease Prevention and Control. If people can be caught in the early stages, it is likely we can prevent the totally devestating collapse that is costing so much in both human and economic terms.

  • Relapse and Remission. The process of remission needs to be studied to help those going into remission make the most of their improvement, and perhaps find the keys to remission. We need information (i.e., statistics) on how frequently those in remission relapse, and how many years a person in remission can go without a relapse, and then have one. Many members of this group had the disease, "recovered", and then when they tried to behave like normal individuals (instead of the 80 percent of normal that these studies are recognizing as "remission"), they relapse. The relapse appears to be worse than the original event. Hence, prevention of relapse would go a long way toward prevention of the worst of this disease.

  • Improvement and Plateau. It would appear that the most common course of the disease is for the victim to be significantly disabled for a period of two years or more, then improve slightly to perhaps 50 percent of former capacities, and then plateau. They remain in the plateau state for an indeterminant period of years.

  • Collapse followed by slow worsening with no remission. A small but significant portion of the CFIDS/M.E. population (10-25 percent) experience collapse followed not by remission, but by a very slow and steady worsening of their condition. British doctors are currently conducting a study called CHROME that has isolated only those patients with M.E. who have been housebound for two years or more and are following their long-range experiences. We need to recognize and study those with the worst variation of the disease.
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Ravn said:
The paper refers to a presentation given by Schweitzer in 1998 about phases in ME. Not sure we've made any progress in further investigating the observations made back then.
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Chrome might have been a useful resource but it makes me cringe that we could identify the housebound for the purposes of observation and natural course investigation but didn’t proceed to do any further research on the severe community for years.
 
Regarding phases of ME ("cfs"), in 1989 Health and Welfare Canada held a workshop, and published the results in 1991.

The introduction says: "The purpose of this meeting is to review what we know about CFS, make recommendations and prepare guidelines concerning the diagnosis and management of CFS, and discuss various approaches for future research."

Of particular interest are pages 59 to 71 of this link.

On page 59 discussion included the issue of clarifying how "chronic psychiatric disease", and "malingering" featured, or did not feature in the Holmes' definition:

http://publications.gc.ca/collections/collection_2016/aspc-phac/H12-21-1-17-S1-eng.pdf

This workshop and the ensuing publication concluded "CFS is a triphasic syndrome: Phase 1 - (lasting 3-6 months), an acute phase of greatest illness. Phase 2 - (lasting 3-24 months), a phase of slow improvement. Phase 3 - stability at an improved functional level usually subjectively less than 100% (no inexorable downhill course)."

Based on the above government information, I was told I would recover in one to three years. I waited, puzzled, and concerned that I didn't seem to be improving, and the three year deadline was fast approaching. Over 30 years on I know this information is at best extremely optimistic for many pwME. We are still waiting for more definitive information about the natural course of this disease.

In August 2009, CFIDS of America reported on a survey of 1,784 respondents: " Only 4.4% have been ill less than two years; 62.1% have been ill more than 10 years....63.3% are fully or partially disabled or retired from work..."

Several other questions including work, full or part-time, receipt of disability income, number of medical consults etc. were also included in the survey.

I have been unable to find the link to the above. I have a photocopy of the info without a link noted. It would be interesting to see more survey results like this one.

The gap between what pwME experience and what policy and decision makers portray is very difficult to describe in positive terms.

However, thirty years on we finally have some good news in Canada.

I hope this more enlightened policy catches on in the UK and elsewhere!

ETA: Also, looking back, by the time I was told I would recover in one to three years, I had been very much worsening for two years, and had had a total of about 6 years of gradual onset with new and increasing health issues added on over time.

Initially, my gradual onset could have been seen as mild ME. With continuing to work, and press on as usual, which included lots of exercise, the ME worsened.

ETA #2: quotation marks added.
 
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DokaGirl said:
This workshop and the ensuing publication concluded "CFS is a triphasic syndrome: Phase 1 - (lasting 3-6 months), an acute phase of greatest illness. Phase 2 - (lasting 3-24 months), a phase of slow improvement. Phase 3 - stability at an improved functional level usually subjectively less than 100% (no inexorable downhill course)."
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This is a description of typical EBV infection which the Americans were obsessed with at that time. Stephen Straus was brought into the CDC and given overall control of the Incline Village outbreak because he was an expert in EBV. The disease was originally thought to be chronic epstein barr disease which was his pet theory and which is described above.

When it turned out that some of the patients had no EBV he was furious and the name was changed to CFS but the definition remained that for EBV with reference to that virus removed.

Regardless, EBV continued to be a focus. There is confusion because EBV may lead to ME but it can also take years to resolve in itself. Like all herpes viruses it can remain in the body for years. Most of the cases of complete recovery I have read have started with being very ill with EBV then improving.

ME as in the epidemics starts with a common infection which seems to be going but then gets worse, often with a relapsing remitting course until it either plateaus or gets worse.
 
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