I have spent some time (probably far too much for my health) drafting and redrafting this letter with some helpful suggestions from members on a members only thread:
https://www.s4me.info/threads/draft-letter-to-the-authors-of-the-nih-pem-study-2020.17052/
The letter refers to a paper discussed here:
https://www.s4me.info/threads/chara...ronic-fatigue-syndrome-2020-nath-et-al.16927/
The letter was also signed by 8 other forum members from 4 countries who asked for their names to be added in support.
I am posting the final version (almost exactly the same as the version on that drafting thread) here to make it public, and will post any reply I receive here.
https://www.s4me.info/threads/draft-letter-to-the-authors-of-the-nih-pem-study-2020.17052/
The letter refers to a paper discussed here:
https://www.s4me.info/threads/chara...ronic-fatigue-syndrome-2020-nath-et-al.16927/
The letter was also signed by 8 other forum members from 4 countries who asked for their names to be added in support.
I am posting the final version (almost exactly the same as the version on that drafting thread) here to make it public, and will post any reply I receive here.
To Barbara Stussman, Ashley Williams, Joseph Snow, Angelique Gavin, Remle Scott, Avindra Nath and Brian Walitt,
NIH
USA
Re “Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome”, 2020, published in Frontiers in Neurology.
Dear Dr Stussman and team,
I am writing to you about your recently published research article. I would like to contribute what I hope is constructive feedback that might explain why you found differences in 'daily' and 'post-CPET' PEM and which might enable you to obtain more detailed responses from patients in any follow-up. I would be grateful if you, Dr Stussman, would forward my letter to the rest of the authors of the article.
I am a long term ME sufferer and carer for my daughter. Between us we have clocked up over 50 years of suffering this disabling chronic illness. For the last few years I have been an active member of patient forums, particularly Science for ME [1]. As a result I have taken a close interest in, and participated in discussions of, all current and some past ME/CFS research, and have shared experiences of living with ME with many patients around the world.
This is a personal letter, which I have shared with members of the forum and edited with their help. Several members asked to be added as signatories. I intend to post it on the public part of the forum along with any reply I receive from you.
I was pleased to read about the NIH in-depth study of ME/CFS, and have been looking forward to reading the results when the study is completed. I was therefore eager to read this first publication from the team, anticipating that after several years working closely with people with ME you would be able to make a significant contribution to medical understanding of the strange and very disabling phenomenon called Post Exertional Malaise.
Imagine my concern then, when I find myself reading a description I don’t recognise of PEM with the bland summing up of PEM into:
“three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints)”
Where was the clear description of ‘malaise’ - the all-encompassing feeling of being very ill that is a core part of PEM and distinguishes it from post exertional fatigue suffered by people with some other conditions, and indeed by people who are simply unfit and take unaccustomed exercise?
Where was the essential observation that PEM leads to a further significant reduction in the sufferer's already limited ability to function, and that this can last for days or longer?
You may argue that these are covered in the details in the paper, but many, if not most, busy doctors don’t read past the abstract. It is therefore vital that any ‘summary list’ of the key features of PEM give a much clearer picture of the reality.
And indeed the description of ME/CFS itself in the first sentences of the abstract and of the introduction are wholly inadequate, not matching any of the most recognised diagnostic criteria for ME/CFS - CCC, ICC or IOM - omitting key features such as orthostatic intolerance, unrefreshing sleep, pain and the fact that the 'fatigue' is disabling, and that PEM is a distinct core feature of ME/CFS.
I have read the full paper, and I think I have identified the sources of fundamental problems with your analysis:
Conflation of daily fatiguability with Post Exertional Malaise in the focus group questions
The questions asked by the facilitator about ‘daily’ experiences of PEM are not about PEM at all, but about an essentially different, though connected, feature of ME/CFS, namely ‘fatiguability’. The wording of the questions makes it clear that they were asking, not about PEM (which is not present every day), but about this daily, indeed constant, feature of ME/CFS.
While this understanding of a distinction between ever-present fatiguability and PEM is not universally agreed across all definitions or between all patients, patient groups [2] and researchers [3], it is, I think, agreed that they are two separate, though related phenomena, and need to be recognised as such in research. The use of the umbrella term PEM to cover both phenomena can lead to data about each being mixed together, with consequent loss of potentially useful insights.
Fatiguabiity means that any activity involving the use of energy, physical or cognitive, or activities that combine both such as social interaction, are experienced by people with ME differently from the experience of healthy people. Regardless of fitness, our muscles and brain seem to run out of energy much faster than when we were well, meaning that as we perform any activity, we experience a rapid diminution in the ability to function.
For example, when walking or standing the legs become ‘heavy’, sluggish, in some patients the muscles become more painful, and after a short period, depending on the severity of the individual’s ME/CFS, the urgent feeling of the need to sit or lie down. And recovery from this back to the state at the start of the activity takes longer than a healthy person experiences.
Cognitive fatiguability means someone with ME/CFS may start, for example, reading an article, but after a paragraph or a few pages, the words stop making sense, or concentration goes, and you forget what you have read. Mental processing slows, concentration drifts, word finding difficulties can occur. As with physical activity, the person needs to rest, giving the brain and body time to recover back to the starting level.
These physical and cognitive increases in symptoms and reduction in function are likely to be combined with orthostatic intolerance, which may mean cognitive activity requires the individual to lie down while doing it, and rests need to be taken lying down.
The answers elicited to these questions about fatiguability may well lead to the machine analysis extracting the three key features you list. But these are daily symptoms of ME/CFS, not specific to PEM.
A person whose ME/CFS is going through a stable phase and who is able to pace successfully will still experience some level of this fatiguability, reducing the ability to function to less than half of what they could manage before they became ill. They may, for a while, with very careful pacing and if their ME/CFS remains stable, only rarely experience PEM, though, even with very careful pacing, this is an unpredictable phenomenon, and even a slight build up of activity over time, or a single instance of pushing through an activity, such as a CPET, may trigger PEM. Other factors such as increased social or emotional pressures, infections and environmental stressors may lower the energy envelope, or the threshold to PEM being triggered.
A person whose ME is less stable or whose life circumstances make pacing difficult may be in a rolling mix of their 'normal' non-PEM ME/CFS state, and PEM. This can make it hard to distinguish between the effects of daily fatiguability when not in PEM, and the symptoms of PEM.
With questions which asked about how patients feel after any daily activity and produced answers about the effect of fatiguability, it was inevitable that a confused picture of PEM resulted. Patients in a group setting are unlikely to want to raise this as a problem, as they will not want to suggest another patient's experience is not 'real PEM'.
Responses from patients to these questions are likely to be a mixture of descriptions of the effects of fatiguability and the effects of PEM, making it impossible to recognise the existence, or distinguish between symptoms of the two phenomena in any analysis.
Incomplete and misleading summary of PEM key features
So what is PEM?
As I and many of my fellow patients on patient forums such as Science for ME understand it, PEM is the phenomenon that occurs, usually with a delay of 12 hours or more, after either a buildup of activity over time, or a single activity that involves pushing beyond one’s energy ‘envelope’. This could be a CPET in a patient with mild ME; having a shower in someone with severe ME; or something so slight as sitting up or turning over in bed in someone with very severe ME.
Contrary to the conclusions reached in your study, PEM, commonly described as a ‘crash’, has at its core far more than the 3 core symptoms of your summary.
It also involves a flare up of symptoms, inadequately described as 'malaise', or a feeling of being ill, normally associated with infections. These may include sore throat, swollen lymph nodes, headache, nausea, dizziness, acute sensory sensitivities, increased symptoms of orthostatic intolerance. Sleep, already unrefreshing, may become more disordered, with 'tired but wired' inability to fall asleep, excessive sleep or sleep reversal.
PEM also includes a severe reduction in the ability to function such that the sufferer may be forced to lie down for a days or weeks in a darkened room, before gradually returning to their normal low level of ME functioning. In some cases PEM may lead to permanent worsening.
As well as the inadequate set of questions, the method of analysis has led to the flawed conclusions. By listing all the ‘malaise’ symptoms separately, but lumping together into just 2 categories, the muscle and cognitive symptoms, these became artificially the ‘core’, while ‘malaise’ appears only on a supplementary list of ‘other symptoms’. Similarly by using the general category ‘exhaustion’, you fail to highlight as a core part of PEM, loss of function.
I would contend that from your paper, just by grouping the symptoms differently, you could have come up with a more valid list of core symptoms of PEM, namely:
- Major reduction in ability to function, often delayed for 12 hours or more after the triggering activities, and lasting a day or usually longer
- Infection-like 'malaise', including additional symptoms such as nausea, loss of appetite, headache, sore throat, heightened sensory sensitivities, disordered sleep and worsened orthostatic intolerance
- Disproportionately severe and prolonged exhaustion
- Significant increase in cognitive difficulties
- Significant increase in neuromuscular complaints such as pain and weakness.
Artificial separation of post-CPET PEM from ‘daily’ PEM
By conflating the ever present daily experience of fatiguability with PEM, the outcome you describe of post CPET PEM being different from PEM suffered by people with ME at other times is, I contend, an artificial distinction built on an inappropriate and inadequate set of questions put to the focus groups. It is an artefact of your methodology, not a real new finding.
PEM is, as I have described, not a daily phenomenon when a patient is pacing successfully - that is the effects of fatiguability.
PEM occurs when a person with ME exceeds their energy envelope and may occur often or occasionally, depending on the individual's circumstances. It is true that CPET is likely to trigger PEM, but so is any activity or series of activities that 'push the envelope'.
The PEM after CPET is not necessarily different from other PEM, the difference your questions elicited is between:
- the non-PEM ME state, in which fatiguability limits activity and causes symptoms,
and
- ME when in PEM which further drastically reduces function and adds and/or ramps up symptoms of malaise, as listed above.
Fundamental study design flaw - inappropriate use of telephone focus groups
Apart from the problems with conflating fatiguability with PEM in the questions, the lumping and splitting of symptoms inappropriately in the analysis leading to an inaccurate list of core PEM symptoms, and artificial separation of post CPET PEM from other PEM, there is also a major flaw in your study design.
As any person with ME is likely to tell you, only those with the mildest ME are likely to be able to sustain concentration and the ability to formulate responses over the duration of a long telephone call, especially with the added factor of interaction with several people during that call. This means participants, however hard they tried to focus and formulate answers in real time, were likely to be suffering the effects of cognitive and physical fatiguability during the call. Such a methodology is highly likely to skew and limit the outcomes. I am surprised and very disappointed that the NIH considered such a methodology in any way appropriate for such a patient group.
Adding this to the flawed and inappropriately leading questions, there is also the added factor of group effect when people are sharing very personal experiences. By, for example, including ‘emotional’ causes and/or effects in the prompts, participants were led to try to think of instances where emotional factors played a part, and once one has shared such an experience, others may feel the need to validate it by coming up with examples of their own, thus artificially creating a factor that may not play a large part in PEM for most patients.
The conclusions drawn from the study:
In your report you have drawn several conclusions, none of which, as I have explained, fit with my understanding of the lived experiences of ME and of PEM.
1. That the core features of PEM are 'exhaustion, cognitive difficulties, and neuromuscular complaints'.
As I have detailed, this is an incomplete list that might limit your findings and interpretation of future research. They leave out the core features of 'malaise' (feeling very ill, with a long list of symptoms) and reduction in function. I think we can make this description more robust, which will increase the rigour and depth of findings, and show valuable patient and public involvement in your research.
2. The deduction that this parallels the experience of post exertional fatigue in other illnesses is therefore flawed, and I contend, unhelpfully inaccurate. I am not aware of any other illness where doing a little more than usual of normal daily activities one day can lead to waking up the next morning with a flare up of 'malaise' symptoms, feeling like you have the flu and being confined to bed for several days. It is not just about being more tired, and aching and a bit foggy headed the next day.
3. The deduction that emotional stresses cause PEM is not demonstrated by the data. The examples given were elicited by a leading prompt, and are of situations where physical, cognitive and social factors are mixed with emotional factors, so the effect of each cannot be deduced.
4. The deduction that PEM resulting from CPET is different from 'daily PEM' is an artefact of conflating fatiguability and PEM in the questions. It is not a new finding, it is a misunderstanding of PEM.
5. The conclusion that separating patients into subgroups according to PEM symptoms may lead to more targeted treatments cannot be deduced from the data in this paper. It is speculation. People with ME/CFS do have variable experiences, but there is no evidence that how patients experience PEM specifically is the key factor in subgrouping.
What next?
I hope you will take the opportunity to maximise patient engagement to co-create any further iterations of this study, using lived patient experience. My comments are offered as part of that engagement process, and I hope you will see them in that light. Any of you and your colleagues are very welcome to join the Science for ME forum to engage directly with a large international group of patients. We are all aiming for the same thing - better understanding of ME and better care and treatment.
I hope, if you decide to do a follow up study to elicit a more accurate description of PEM in ME/CFS, you will take all my points into careful consideration, and ensure that there are no leading questions, artificial distinctions and inappropriate lumping and splitting of symptoms into categories that can lead to a misleading analysis and conclusions.
The first step in that is, I think, defining clearly what you mean by PEM. Is it an umbrella term for any aspect of ME/CFS that can be attributed to activity, physical, cognitive, social, emotional etc? Or is it the specific phenomenon that recognises the existence of a (sometimes unpredictably shifting) energy threshold, or energy envelope, and describes what happens to people with ME, usually with a delay, after they exceed that threshold?
Since all existence requires some level of 'activity', using the first definition in studying the symptoms of PEM is in danger of simply leading to a listing of the symptoms of ME/CFS itself, which, since ME is an illness defined by lists of symptoms, can lead to circular reasoning, with the resulting list of core symptoms depending more on how the data is grouped and split in the analysis, rather than enabling greater insight into the complexity of living with ME/CFS.
I hope also you will take on board my concern about the inappropriateness of relying entirely for data on focus groups by telephone. Respondents of all levels of illness severity should be equally enabled to take part by providing them with a choice of feedback methods that enable them to participate at their own pace with time to reflect and recover between answering questions.
People with ME have suffered over 30 years of gaslighting by doctors and therapists determined to put their own spin on what we are experiencing as patients. It is heartbreaking to see the NIH falling into the same trap of using inappropriate data collection methodology and flawed analysis which I fear will lead to further gaslighting, as doctors deduce that all PEM involves is a short period of tired muscles and brain and feeling ‘exhausted’. It becomes all too easy for doctors to read the abstract and say, ‘I feel tired after a busy day at work too’. Or ‘this sounds the same as fatigue suffered in other chronic illnesses’. We need better than this.
References:
[1] Science for ME forum
https://www.s4me.info/
[2] MEA Summary Review: Assessing PEM (Post-exertional malaise)
https://meassociation.org.uk/wp-con...ch-Review-Assessing-PEM-in-MECFS-25.03.19.pdf
[3] Dialogues for a Neglected Illness - Post Exertional Malaise
https://www.dialogues-mecfs.co.uk/films/post-exertional-malaise/
Thank you for reading my letter,
Trish Davis, United Kingdom
Signed in support by:
8 members listed with their country.
