Evaluating case diagnostic criteria for ME/CFS: toward an empirical case definition, 2022, Conroy, Jason et al

Abstract

Purpose
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a variety of symptoms including post-exertional malaise, unrefreshing sleep, and cognitive impairment. A variety of case definitions (e.g., the Canadian Consensus Criteria (CCC), the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC), and the Institute of Medicine (IOM) criteria) have been used to diagnose patients. However, these case definitions are consensus-based rather than empirical.

Materials and methods
The aim of the current study was to evaluate the validity of the aforementioned case definitions by factor analyzing a large, international sample (N = 2308) of ME/CFS symptom data. We performed primary and secondary exploratory factor analyses on the DePaul Symptom Questionnaire's 54-item symptom inventory. These results were compared to the CCC, the ME-ICC, and the IOM criteria.

Results
We identified seven symptom domains, including post-exertional malaise, cognitive dysfunction, and sleep dysfunction. Contrary to many existing case criteria, our analyses did not identify pain as an independent factor.

Conclusions
Although our results implicate a factor solution that best supports the CCC, revisions to the criteria are recommended.

• Implications for rehabilitation
• ME/CFS is a chronic illness with no consensus regarding case diagnostic criteria, which creates difficulty for patients seeking assistance and disability benefits.
  
  
• The current study compared three commonly used case definitions for ME/CFS by factor analyzing symptomological data from an international sample of patients.
  
  
• Our results suggest three primary and four secondary symptom domains which differed from all three case definitions.
  
  
• These findings could help reduce barriers to care for those disabled with ME/CFS by guiding the development of an empirically-based case definition.

Paywall: https://www.tandfonline.com/doi/abs/10.1080/09638288.2022.2043462

 

"These results most closely support the CCC, while there was less empirical evidence for the ME-ICC. While the IOM criteria was empirically supported, having the choice of cognitive impairment and/or orthostatic intolerance is a limitation, as our results suggest that cognitive impairment is a more fundamental symptom. The IOM criteria have also been critiqued for lacking exclusionary illnesses. The results of our analyses make clear the need to revise the IOM criteria, a point further highlighted by the IOM committee's suggestion to revise the criteria in no more than five years once evidence had been collected. Our recommendation would be for the IOM criteria to continue serving as a clinical case definition. However, we recommend that for research purposes the IOM criteria incorporate exclusionary illnesses similar to prior ME/CFS case definitions, as well as require cognitive impairment alone rather than cognitive impairment and/or orthostatic intolerance."
(My bolding.)

 

Biomarkers. We need biomarkers.

 

Funded by - National Institute Of Neurological Disorders And Stroke of the National Institutes of Health under Award Number R01NS111105. So why not open access ?!?

 

It has been discussed here before but I have concerns over what Jason and his team are grouping under the banner of PEM which are, from the paper;

Dead, heavy feeling after exercise
Next day soreness after activity
Mentally tired after slight effort
Minimum exercise makes you tired
Physically drained after activity
Fatigue/extreme tiredness
Unrefreshing sleep

 

Yes, I echo @Andy, it is so important to distinguish between increased fatiguability and PEM, as the former is found in many conditions whereas the latter is characteristic of and possibly unique to ME.

Without this understanding it is impossible to address the validity/reliability of diagnostic criteria.

 

His papers usually are available on PubMed within 6-12 months. I think NIH-funded researchers are even required to do this.

 

I'm no longer convinced that PEM can be safely assumed to be unique to ME/CFS, or that clinicians can distinguish PEM from tiredness after exertion. Exclusionary conditions seem like a bad idea however. Having ME/CFS doesn't make you immune to other illnesses, some of which might be easier to diagnose than ME/CFS.

Having an illness listed as excluding the possibility of ME/CFS also sends the message that it's very hard to distinguish that illness from ME/CFS. So what message is being sent by listing all sorts of conditions as exclusionary? That ME/CFS is a very vague concept and hard to distinguish from say schizophrenia (one of the exclusionary conditions in one of the diagnostic criteria if I recall correctly).

Instead I think we should develop a good questionnaire to detect PEM that correlates with 2-day CPET findings. I'm sorry to say but my feeling is that Jason is not the right person for this because his definition of PEM is too unspecific.

A good PEM questionnaire would focus on the unusual aspects of PEM like the delay or symptoms such as heightened pain perception, changes in heart rate and sleep, as well as the impact on ability to function, and the overall pattern of symptoms worsening. It would avoid unspecific descriptions like "feeling dead after exercise" or rapid fatigueability.

There may also exist multiple types of PEM that we can't distinguish yet.

 

To your second point above, PEM after cognitive or other stressors may be different from that after physical activity so a questionnaire that correlates with 2-day CPET findings may be too narrow

 

In terms of diagnosis for individuals - as opposed to selection for research, biomarkers may be as problematic as they are helpful.

At this stage we have no idea whether we are talking about a single condition with a single sequential pathophysiology for which a single biomarker would provide a unique line of separation between 'have ME/CFS' and 'not have ME/CFS', or whether ME/CFS as we currently define it is actually a package of multiple conditions that require multiple biomarkers to separate multiple pathophysiologies.

Given the heterogeneity of symptoms, the indications are that at best multiple subtypes of ME/CFS are in play and even if there is a major leap in understanding ME/CFS there may still be great difficulty in achieving diagnosis by biomarker across even subtypes, let alone potentially entirely distinct disease processes. Additionally there needs to be caution about the process of biomarker development - a good summary here: Biomarker definitions and their applications https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5813875/

Diagnosis by symptoms, done intelligently and sympathetically is probably going to remain the best option for most PwME for at least the next few years and therefore it's worth investing some research effort to ensure the best approaches are being applied.

 

So in essence, what he's saying is that the NICE 2021 criteria should be the clinical criteria used by all (as it meets the requirements for improving the IOM he outlines)?

Though, I should add, we describe PEM more narrowly than he does, so he may disagree with that (but I'm sure most patients would prefer our version).

 

Some of Jason's descriptions of PEM happen to me everyday, several times per day, but I don't count myself in PEM, until I crash.

To my knowledge, unrefreshing sleep in Jason's PEM list is ongoing for PwME, not just as a part of PEM.

Conveying the difference between how a pwME feels, and how a reasonably healthy person feels has of course, been one of the main problems all along.

 

I only count myself as being in PEM when there is noticable worsening of one day from the next, and on the previous days I did more than usual. Or if symptoms start during or shortly after exertion and persist for days but that is rare because it requires more overexertion.

That means when I walk with a funny gait due to weakness that appears after a walk outside, it's not PEM. Or when I become exhausted and unwell from household work.

 

Unrefreshing sleep is so trivial compared to the problems we have. The constant insomnia, vivid dreams, pain, spasms, inability to bear the weight of the bedcovers, night sweats, headaches, air hunger, dry eyes, tinnitus, all reduced to "unrefreshing"

I dread night times.

 

Interesting. To help me understand, can you explain the way in which NICE 2021 describes PEM more narrowly than Jason?

And do you see any differences between how NICE 2021 and the IOM or NIH CDE describe PEM (see below). I'm trying to understand where we might want to push to get tighter international alignment on how PEM is described.

From the IOM -

• PEM is a worsening of a patient’s symptoms and function after exposure to physical or cognitive stressors that were normally tolerated before disease onset. (they discuss the range of exacerbated symptoms and also other triggers - emotional, standing up for an extended time, etc)
• Trigger: "The type, severity, and duration of symptoms may be unexpected or seem out of proportion to the initiating trigger
• Time to onset: Although PEM may begin immediately following a trigger, patients report that symptom exacerbation often may develop hours or days after the trigger has ceased or resolved.
• Duration: PEM is unpredictable in duration, potentially lasting hours, days, weeks, and even months

From the NIH PEM CDE - here
Post-exertional malaise is an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:

• Exacerbation of some or all of an individual study participant's ME/CFS symptoms. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), unrefreshing sleep, muscle pain, joint pain, headaches, weakness/instability, light-headedness, flu-like symptoms, sore throat, nausea, and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
• Loss of stamina and/or functional capacity
• An onset that can be immediate or delayed after the exertional stimulus by hours, days, or even longer
• A prolonged, unpredictable recovery period that may last days, weeks, or even months.
• Severity and duration of symptoms that is often out-ofproportion to the type, intensity, frequency, and/or duration of the exertion.

For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM. Some other precipitants of PEM that have been identified include positional changes and emotional stress. In some instances, the specific precipitant cannot be identified. The threshold for a precipitant to trigger PEM can vary between individuals as well as within the same individual, at different times during their illness.

 

I assume this is the paper that Dr. Jason is going to talk about in the webinar scheduled for March 16.

https://www.s4me.info/threads/webin...itions-for-long-covid-dr-leonard-jason.24839/

 

a few things seem to cause issues for us.

- variety of experience of those who have m.e. [cover some, lose others]
- range of severity [if yu do cpet on some then you kill them]
- what pem means
- whether pem is necessary, sufficient, both, or neither
- words seeming like ordinary healthy person experiences
- words conveying the experience of some severity leves bt not others
- words being ambiguous, vague, etc.

fwiw there seem to be a few meanings of empirical, which is in the title of hte paper. it's not /remotely/ as bad as comorbidity or pem [or hysteria and mental illness and psychogenic and psychological] but still:

- let's try it to see if it works [doctor tries leeches]
- based on observations 1 [jason does quetionnaire instead of doctors ... hobnobbing using delphi process?]
- based on observatins 2 [jason calls this consensus]
- whatever reeves definition meant

those are not confused in this case but i would not want those to get confused including deliberately.

those seem confusable with health. the order is off. those could be a marathon or all nighter.

the concept of pem is much too confused i think; is it useful? non-rhetorical: what would you do pre-biomarker to define sle without butterfly rash? or wegener's whatever it is called tehse days? are severe in study?

 

One thing for sure is that you don't have to be moderate or severe to get PEM. Your health can be improving up to 90% and you will still experience severe PEM.

Also, PEM doesn't necessarily present itself for years after M.E onset.

 

Maybe it means relative to whatever is baseline?

My sleep is never good, even on "good" days, but it is definitely worse during PEM.

Paradoxically (when compared with "normal" folks) my sleep improves when I substantially increase my rest for at least a few days in a row (the longer I can do it, the better sleep gets). "Increased rest" here means basically nothing other than eating/sleeping. I even skip bathing for a day or two when I need to get some extra rest.

By contrast, the night sweats (less common now than during those first 5-6 years) only hit me when I'm in a PEM crash.

Also, my sleep has completely changed when compared to the first few years of illness. I used to sleep 14? 16? hours a day during those first couple of years, especially during my worst period in 1991 when I was almost bedbound (used to drag myself to the couch because I hated being in bed all day).

 

This is true for me too. My sleep is always prone to disruption but only during a 'flare up' or a 'relapse' following over-exertion (ie PEM) am I woken in the night by pain or flu-like symptoms. My night time sleep is longer and deeper when I also have a two or three hour nap in the afternoon. This latter is the reverse of what would have happened before my illness.