Open Survey: Assessing Attitudes Toward Case Definitions: Consensus Building Amongst Researchers, Physicians, Patients, and Activists - Lenny Jason

Andy

Andy

Retired committee member
"Many controversies have emerged around the development of case definitions for ME, ME/CFS, and CFS. We have developed this brief questionnaire that assesses key issues involving case definitions. Thank you for the time you have provided us to give us feedback on these important issues for the patient and scientific community."

"What is the purpose of this research?

We are asking you to be in this research study because we are trying to learn more about perspectives on myalgic encephalomyelitis/chronic fatigue syndrome (ME, ME/CFS, and CFS) case definitions, cardinal symptoms, as well as other issues relevant to ME and ME/CFS research and policy. This study is being conducted by the Center for Community Research at DePaul University under the supervision of professor Leonard A. Jason. We are a research team at DePaul University that has been studying ME, ME/CFS, and CFS for decades."

https://redcap.is.depaul.edu/surveys/?s=4CCENA4KHL

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I thought the survey was ok. There is room for comments.

I'm not too sure how useful the results will be. If a majority of people want a particular diagnostic criteria used, or think ME is or isn't the same as CFS, will it change anyone's mind? They are aiming for a sample of 2000 people across people with ME/CFS, researchers and clinicians. It seems to me it would be quite easy to get a skewed sample with the survey being spread by internet connections.

Perhaps it will help indicate that PEM is important and Fukuda shouldn't be used.
 
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Questions I had issues with.

"Do you believe that ME is a separate illness from either CFS or ME/CFS?" Answer Yes or No

"Do you believe that ME, ME/CFS, and CFS are three separate illnesses?" Answer Yes or No

Confusing. Asking about three separate things in each question and then only offering two options. What if someone thinks, for example, that ME and CFS are the same? If they do then they can't express that opinion. Should have offered all the options as possible answers, i.e. all three are the same illness, X and Y are same, X and Z are same, Y and Z are same, none are the same.


"Do you feel that patients should be differentiated into those who meet a case definition requiring post-exertional malaise versus case definitions where post-exertional malaise is either not mentioned or included as an optional/minor criterion? This issue was discussed in a recent study by Wormgoor and Rodenburg 2021." Answer Yes or No
Thread discussing the study linked to, The evidence base for physiotherapy in myalgic encephalomyelitis/chronic fatigue syndrome when considering PEM: a systematic review (2020) Wormgoor

"Do you think that to meet a research case definition there should be some exclusionary conditions?" Answer Yes or No

And I think there should have been an "I don't know" option for the two questions above.


And finally, I'm not even sure what is meant here. Is it that they are asking whether a case definition, for example, should ONLY include long duration and exclude short duration, or are they asking whether a case definition should be split into long duration and short duration subtypes? The use of the word include suggests the former to me.

"Do you think the case definition should include certain subtypes? (Select all that apply)

Duration of illness (long duration vs short duration)
Onset type (eg., infectious onset, Epstein Barr Virus onset, stress onset, sudden onset, gradual onset, etc.)
Trigger type (eg., Mold, Lyme disease, etc.)
Comorbidities (eg., comorbid Long COVID, fibromyalgia, multiple chemical sensitivities, etc.)
Severity of illness (eg., mild, moderate, severe (housebound) and very severe (bedbound))
Course of illness (eg., symptoms are persistent, recurrent, fluctuating, constantly getting worse, constantly improving, etc.)"
 
Yeah, when I answered those questions, I assumed it meant having defined subtypes e.g. for severity: mild, moderate, severe, rather than excluding subtypes. But I agree, that set of questions is confusing.

For duration, I was thinking of the Hornig study, the less than 3 years; more than 3 years distinction, and I thought well, that doesn't need to be in a diagnostic criteria for research. There's nothing to stop researchers adjusting and subsetting criteria if it helps answer their research question. So, I said 'no', it doesn't need to include subtypes by duration.

But, I forgot about the need to not include everyone who feels fatigued a week or a few weeks after an acute illness. There does need to be some requirement for the symptoms to have existed for some months. So, I stuffed up there.
 
Here are the comments I put at the end, for what they are worth.
If you haven't submitted yours yet, it may be better not to read them if you don't want to be influenced.


==========

I have said there should be exclusions for a research definition but would like to highlight that I wouldn’t necessarily want the same exclusions for a clinical definition or clinical practice. Similarly for what it is worth, I would be willing to accept a clinical set of criteria that was looser.

It doesn’t fit in with the options but I would like to like to see composite scores used for symptom criteria so it is not all or nothing with regard to symptoms. A lot of symptoms are not ubiquitous in patients but are common and it increases the confidence that a patient has the condition if they have the symptom. Also scoring for each symptom would be based on the frequency and severity of the symptom. So you might enquire about maybe 10-30 symptoms. And the possible scores might be 0 to a number in the hundreds. Then a threshold could be arrived at for a definition. But individual research studies could also look at the data by stratifying or subgrouping by different symptom scores. Also each symptom wouldn’t necessarily need the same weighting i.e. a particular symptom that was considered as better at distinguishing the illness from other conditions might get a weighting of 2/3/4/whatever.

It is possible with such a system that I would be happier with fewer required symptoms. I think for various reasons people may focus on some symptoms but not focus on or report others but still have them. For example, early on in my illness when I was undiagnosed, I really missed exercising and was really focused on trying to exercise more so was very focused on symptoms that stopped me doing that like what seemed like muscle sprains. I ignored some other symptoms.

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I have picked up from Prof Jason that he isn't into symptom counting but that doesn't necessarily mean he is correct.
 
Is the case definition an actual problem? As in, does finding consensus, impossible in the current context, get us any further? Does it lead to any improvement for patients? Make better research? Doubtful, since anyone can make the choice to any case definition they want, apparently. And it conflicts with both training and culture that it's all mood disorders, or whatever. 99% of physicians clearly don't care, they need this to be formal, they need a test, a test that is recognized, politically and professionally acceptable. They need validation from their peers that what they are doing is worth doing, and chronic illness is explicitly excluded from that.

What does get medicine to make a move? A biomedical breakthrough. I'm sure the same issues were common with things like ulcers and pre-breakthrough autoimmune diseases, endless debate about how to make a case definition. It shouldn't be this way, but this is the reality we have to deal with. Debating is for entertainment. We could keep debating this for decades and it wouldn't get anywhere.

I really think the idea of finding consensus is impossible. Not without a complete paradigm shift. Where we are is basically like the last episode of Game of Thrones, where (roughly) the idea that patients should have any say about their health is subject to raucous laughter. Small people are meant to be rules. By rulers. There is no consensus to be had here any more than it's possible for NASA to find consensus with astrologers. We are simply not working on the same set of problems, and none of our detractors are interested in what's real, they like the imaginary models too much for this.
 
Yes, I agree. Trying to refine criteria when we don't even have basic epidemiology, let alone biology, is mostly wasting time.

I'd prefer it if Professor Jason focussed more on really good epidemiological studies rather than this naming stuff. I understand that it can feel a bit like a chicken and egg problem - 'how can we study it if we can't name it?'. But, just using one of the criteria with PEM as a base for selection (I like the SEID one), and collecting information about other symptoms - it would be possible to make progress.

For example, there could be a study that tracks people from the earliest possible time in their illness (so perhaps using the people identified in prospective studies), surveying their symptoms. What symptoms are there from the very beginning? Do other symptoms come along later? Do there seem to be subsets? Differences between males and females? How does the illness fluctuate? How many people improve or no longer have the illness at various times after onset? How many people give up work? So, a study a bit like those famous studies where they take a set of babies and track them over time across their lives, conducting all sorts of studies that the longitudinal structure makes possible.

There are loads of good possibilities.

More prospective studies, perhaps with Long Covid.

I'd like to see prevalence studies in other cultures/other languages. Are there traditional understandings of the illness; what symptoms are important in those understandings? Those might present interesting challenges for people interested in naming.

Track symptoms/activity levels in women over time and correlate with the menstrual cycle.
Track symptoms/activity levels over pregnancies....
 
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I agree tracking studies would have more value.

Being cynical, I can see why studies like this survey are more attractive to set as research student projects, as they cost nothing and can be done online in one go with no complications like ethics and proper sampling methods to ensure representative samples and no follow up over much longer time scales.
 
Tom Kindlon said:
Here are the comments I put at the end, for what they are worth.
If you haven't submitted yours yet, it may be better not to read them if you don't want to be influenced.


==========

I have said there should be exclusions for a research definition but would like to highlight that I wouldn’t necessarily want the same exclusions for a clinical definition or clinical practice. Similarly for what it is worth, I would be willing to accept a clinical set of criteria that was looser.

It doesn’t fit in with the options but I would like to like to see composite scores used for symptom criteria so it is not all or nothing with regard to symptoms. A lot of symptoms are not ubiquitous in patients but are common and it increases the confidence that a patient has the condition if they have the symptom. Also scoring for each symptom would be based on the frequency and severity of the symptom. So you might enquire about maybe 10-30 symptoms. And the possible scores might be 0 to a number in the hundreds. Then a threshold could be arrived at for a definition. But individual research studies could also look at the data by stratifying or subgrouping by different symptom scores. Also each symptom wouldn’t necessarily need the same weighting i.e. a particular symptom that was considered as better at distinguishing the illness from other conditions might get a weighting of 2/3/4/whatever.

It is possible with such a system that I would be happier with fewer required symptoms. I think for various reasons people may focus on some symptoms but not focus on or report others but still have them. For example, early on in my illness when I was undiagnosed, I really missed exercising and was really focused on trying to exercise more so was very focused on symptoms that stopped me doing that like what seemed like muscle sprains. I ignored some other symptoms.

==========

I have picked up from Prof Jason that he isn't into symptom counting but that doesn't necessarily mean he is correct.
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I forgot to mention the Bansal criteria in my submission.
He uses symptom scoring.
He proposes a threshold of 8+ out of 13 for clinical criteria and 10 out of 13 for research criteria.
I think having stricter criteria for research/looser criteria for the clinical scenario is justified.



Table 2 Details of the important symptoms that characterise CFS/ME and their respective scores. See text for further details

Factor Score

Delayed prolonged post-exertion malaise after
increases in physical, mental & emotional activity
3

Non-restorative sleep with frequent difficulty
initiating and/or maintaining sleep
2

Impaired concentration that is reduced further
by external stimuli
1

Reduced short term memory with word finding
difficulty
1

New onset headaches (>2/mth and different in
character from
previous headaches)
1

Sore throat with cervical tenderness/recurrent
flu-like episodes
1

Arthralgia affecting several joints with stiffness >1 hr
but no swelling
1

Myalgia affecting multiple groups and exacerbated
by mild exertion
1

Postural instability feeling unstable on standing,
prolonged standing or sitting
1

Hypersensitivity to sounds and lights (smells and
to a lesser degree taste also)
1
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Using the CFS/ME scoring criteria

The diagnosis of CFS/ME in adults is based on the presence of variably disabling fatigue of at least 4 months duration (6 months outside of the UK) and 8 or more from 13 points awarded for each of the symptoms and factors detailed in Table 2. However, there is an absolute requirement for some form of post-exertion malaise (PEM) after physical, mental and emotional over activity. To attract the maximum 3 points the PEM must be delayed by at least 12 h after the completion of the specific activity and the extra fatigue and additional ill health must be prolonged with a duration exceeding 24 h. Note that in children the PEM can be immediate and particularly in the very young children. If the PEM is more immediate and certainly less than 3 h after extra activity but the duration is still over 24 h then 2 points are awarded. A rapid PEM (<1 h) lasting less than 24 h gives 1 point. Alternative causes of the fatigue must be considered if it occurs simultaneously and commensurately with the physical over activity and particularly if there are any cardiorespiratory symptoms.

Unrefreshing sleep is a frequently reported by both young and old patients with CFS [26–28] and a disturbance of sleep has been demonstrated on polysomnography by several investigators [29–32]. Many CFS subjects also suffer difficulty with sleep initiation and maintaining sleep [29, 32]. A demonstrable reduction in the percentage of stage 4 sleep was evident in these patients on polysomnography [29]. Non-restorative sleep (NRS) affects over 90 % of patients with CFS/ME and often occurs in most, if not every, night. It is important that obstructive sleep apnoea, frequent waking from pain and urinary symptoms are excluded as a cause of NRS. Sleep studies are recommended if there are concerns as to the importance of sleep disturbance in those with chronic fatigue. This is important as recent work suggests that a primary sleep disturbance may explain fatigue in almost a fifth of patients with Fukuda criteria confirmed CFS/ME and is a comorbid problem in a similar proportion [23]. Two points are given if the NRS is accompanied by difficulty initiating and maintaining the sleep at night time and these difficulties are evident for 5 or more nights per week. However, if the NRS is not accompanied by difficulty initiating or staying asleep this gives 1 point. In both cases the non-restorative nature of the sleep disturbance must persist with hypnotics which many patients use to initiate sleep.

Regarding, the neurocognitive problems faced by those with CFS, the two that appear to be most disabling are the impaired concentration and short term memory. These are aggravated by extraneous noise, bright lights and movement. Word finding difficulty is especially frequent and ‘following’ a conversation is often mentioned as being difficult especially one involving an unfamiliar topic. Both the reduced concentration and the impaired memory are given one point each although it may be argued that the two are related. Thus concentration is required to acquire memory and the latter may be reduced because of problems with the former. Notwithstanding, we have recently shown that deficits in recall are more significant for retrospective than prospective memory and that fatigue, depression and general efficacy were most linked with cognitive failures [33].

The aching of the muscles of the axial and appendicular skeleton has a quality similar to that experienced when an individual has a viral infection. The muscle creatine kinase is normal and while there is no clear evidence of muscle damage, some have reported mitochondrial abnormalities [34] and virus like particles. In the absence of fibromyalgia there is no significant and painful tenderness of the muscles. The latter can be seen in polymyositis which like many of the systemic connective tissue disorders can be accompanied by fatigue in a significant proportion of patients [35, 36]. The arthralgia in CFS/ME is rarely accompanied by joint swelling and there is no synovitis. The majority of patients mention stiffness of the joints which can last over one hour in the morning. Both the myalgia and the arthralgia give one point each only if these symptoms are evident for more than half of the patient’s waking hours and the myalgia is aggravated by low level activity.

The mechanism of the hypersensitivity to lights and sounds and sometimes smells is unusual and this symptom is rarely seen in any other condition. In this respect some patients with significant CFS/ME may chose to wear sunglasses even in normal daylight. For some the hypersensitivity to smells contributes to their continual nausea. It is unclear whether the myalgia and arthralgia reflect a general hypersensitivity to all sensory stimuli but both need to be present for more than half of the waking time to attract one point each. Many CFS/ME patients report that their joint pain is accompanied by stiffness which lasts for hours and may be present all the time. The joint stiffness in rheumatoid arthritis and the recognised connective tissue disorders is nearly always worse after rest and inactivity and in the morning tends to last only a couple of hours or so. In these conditions synovitis with swelling and warmth of the joints is often seen and particularly with acute flares of disease activity. In contrast joint swelling and warmth was rarely, if ever, seen in any of our CFS/ME patients. Where there is doubt, blood tests looking for inflammation, immune activation and autoimmunity can be very helpful.

Sore throat and flu like sensations have been suggested to support the notion that CFS/ME is due to an unrecognised viral infection that activates recurrently. However, throat swabs rarely prove positive for either bacteria or the commonly recognised viruses. Regardless, the sore throat is frequently associated with tenderness of the anterior and sometimes posterior neck although actual lymphadenopathy is frequently absent. To score a point this symptom must be evident one or more day per week and for at least the previous four months. In reference to the flu like sensations these often cause aching of the body and with a low grade fever or sensation of being hot and sweaty. In my experience these can last several hours at a time and occur at least once per week in over two thirds of patients. The presence of eight or more points out of thirteen gives a high probability that the patient has CFS/ME.

For research studies I would suggest that subjects should have ten or more. This is the case for the research undertaken at this institution. In borderline cases where the subject has prolonged unexplained fatigue but scores only 7 points, the presence of certain other unusual features may be used to confirm the diagnosis of CFS/ME. These include alcohol intolerance, hypersensitivity to medications, perpetually cold hands and feet and an unusual recurrent sighing pattern of respiration.

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Assessing chronically fatigued patients with borderline scores Additional features that may suggest CFS/ME in those with borderline scores include alcohol intolerance which we see in four fifths of our patients. This often commences soon after the onset of the CFS/ME symptoms. In the only other report on this issue, Wooley et al. [37] reported 67 % of their 114 patients with CFS reducing their intake of alcohol as it made their fatigue worse. In our experience nearly all patients with CFS have reduced their intake of alcohol and I have not seen a single patient who had increased his/her alcohol intake. Moreover, tolerance of 4 units or more of alcohol in a single sitting is unusual and encourages us to revaluate the diagnosis. In this regard fewer than 20 % our patients continue regular alcohol ingestion although even here the amount consumed has been decreased.
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