Latent class analysis of a heterogeneous international sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome (Leonard Jason team)

[Dolphin]

Frank Twisk replied:

F.N.M. Twisk (2018): Letter to the Editor, Fatigue: Biomedicine, Health &
Behavior, DOI: 10.1080/21641846.2018.1507699

Extract:

Not surprisingly, none of the subclasses relates to a ME patient subgroup [2]. This is a direct consequence of the definition of ‘ME/CFS’ [1]. ME is a neuromuscular disease, characterized by muscle fatigability (‘general or local muscular fatigue following minimal exertion with prolonged recovery time’) and ‘neurological disturbance, especially of cognitive, autonomic and sensory functions’ [3,4]. ‘ME/CFS’ is defined by the authors by four ‘core symptoms’: fatigue, post-exertional malaise (PEM), neurocognitive problems, and unrefreshing sleep [1]. Using this definition of ‘ME/CFS’ a ME patient subgroup is excluded, as a large patient study (n = 420) [3] found that only 77% of ME patients experience ‘cognitive disturbance’.

[3] Dowsett EG, Ramsay AM, McCartney RA, et al. Myalgic encephalomyelitis - a persistent enteroviral infection? Postgrad Med J. 1990;66(777):526–530. PMID: 2170962. doi:10.1136/pgmj.66.777.526.

I remain to be convinced that cognitive symptoms should not be a requirement. It seems to weak to base this on one study. It would be interesting to see the particular wording. The studies I recall in recent years had a much higher rate of cognitive symptoms.

 

[Trish]

I'm not sure about whether cognitive symptoms should be a requirement for ME diagnosis as you suggest, @Dolphin.

Some of us have the rapid muscle fatigueability, pain, orthostatic intolerance, unrefreshing sleep, etc, and, most importantly, very clear PEM, but don't seem to have very noticeable brain fog except during PEM.

Where does that leave us? Are we a subgroup, or do we have a different condition that should be called something else? In the end, until we have objective biomedical tests, we can't know whether we all have the same condition, or ME is and umbrella term for a group of conditions. I don't think it's particularly helpful to start trying to exclude some pwME by specific symptom.

Also, how do you know if you have brain fog if it's at the milder end of the spectrum, and there are no objective tests for it. More severe brain fog is clearly awful and very disabling, but the milder end presumably overlaps with normal ranges of memory and concentration.

 

[adambeyoncelowe]

@Dolphin, thanks for wading through this.

A few thoughts:

Jason is resisting the notion that counting the number of symptoms can be used as an indicator of severity. You wondered why this might be. I'm wondering whether it's that old psychiatric belief that 'more symptoms = more likely to be psychosomatic' getting in the way.

Maybe he feels counting symptoms will include too many of these 'psychosomatic' patients? My feeling is that this is a nonsense concept, given weight because people with more complex symptoms will also have more complex illnesses, which cursory investigations may not capture. (I.e., I don't really believe there's much evidence for purely psychogenic somatic illnesses.)

You mention the Twisk comment. I'm with you that one study (which still shows that 77% of patients do have brainfog) doesn't mean brainfog isn't a core symptom.

However, perhaps more importantly, we don't know what the basis for this four 'core' symptom criteria are. It's unlikely to be the SEID definition (which Jason doesn't seem to like, considering his papers on subject), but in that definition, it's a choice of OI or cognitive problems, not necessarily both. Is that the case here? Do we know whether the paper requires all four 'core' symptoms to be present in everyone or does it require, for example, three out of four?

Lastly, is there a quick and concise summary of each subgroup?

Edited: second use of 'symptoms' should have been 'illnesses'. Now corrected.

 

[Dolphin]

@Dolphin, thanks for wading through this.

A few thoughts:

Jason is resisting the notion that counting the number of symptoms can be used as an indicator of severity. You wondered why this might be. I'm wondering whether it's that old psychiatric belief that 'more symptoms = more likely to be psychosomatic' getting in the way.

Maybe he feels counting symptoms will include too many of these 'psychosomatic' patients? My feeling is that this is a nonsense concept, given weight because people with more complex symptoms will also have more complex symptoms, which cursory investigations may not capture. (I.e., I don't really believe there's much evidence for purely psychogenic somatic illnesses.)

Yes, he has expressed that concern before.

 

[Trish]

Some of us have the rapid muscle fatigueability, pain, orthostatic intolerance, unrefreshing sleep, etc, and, most importantly, very clear PEM, but don't seem to have very noticeable brain fog except during PEM.

Or maybe we have brain fog but interpret it differently. I've just read a conversation on Twitter in which people are sharing their experiences of 'bad brain fog' including things like putting things in the wrong place and completely forgetting you've done so. I do this often, but simply put it down to normal absent mindedness. Similarly, a new carer introduced herself the other day, and within seconds I'd forgotten her name. But I've always done that - it's normal for me.

 

[arewenearlythereyet]

Or maybe we have brain fog but interpret it differently. I've just read a conversation on Twitter in which people are sharing their experiences of 'bad brain fog' including things like putting things in the wrong place and completely forgetting you've done so. I do this often, but simply put it down to normal absent mindedness. Similarly, a new carer introduced herself the other day, and within seconds I'd forgotten her name. But I've always done that - it's normal for me.

I suffer from cognitive problems both in PEM and out. What I’ve noticed though is that the severity increases with PEM this manifests as:
Confusion (I.e. can’t think straight)
Poor concentration
Poor hand to eye coordination
Blurred vision
Sensitivity to light
Sensitivity to sound
Poor memory

I track these separately. What I’ve noticed is that all of these coincide and are heightened with PEM but only some are present all the time as a continual base symptom that fluctuates from day to day (confusion, poor concentration and memory loss)

I think you could iron out questionnaire error by making the subjects carry out a tracker symptom diary. I’m surprised that any author would publish without sense checking responses in some way? This is particularly odd since the symptoms wax and wane over time?

Personally I think cognitive dysfunction is/are one of my most restrictive symptom/s so excluding it seems a little weird particularly as it’s so common?

 

[Trish]

Personally I think cognitive dysfunction is/are one of my most restrictive symptom/s so excluding it seems a little weird particularly as it’s so common?

I wouldn't dream of suggesting excluding it from criteria as a very commonly experienced disabling symptom in ME that can help with diagnosis. I am just suggesting that it not be mandatory for ME to be diagnosed, at least until we have clearer tests for cognitive dysfunction and clearer tests for ME itself. I would put it in the same group with pain and orthostatic intolerance - very common symptoms of ME, but not mandatory.

But it's not up to me.

 

[Dolphin]

However, perhaps more importantly, we don't know what the basis for this four 'core' symptom criteria are. It's unlikely to be the SEID definition (which Jason doesn't seem to like, considering his papers on subject), but in that definition, it's a choice of OI or cognitive problems, not necessarily both. Is that the case here? Do we know whether the paper requires all four 'core' symptoms to be present in everyone or does is require, for example, three out of four?

It is unclear to me whether there were any requirements for specific symptoms:

International convenience samples of ME/CFS patients were assembled. Methods of case ascertainment are described below (more detailed information can be found in Jason et al. [20]). See Table 1 for demographic characteristics of the combined sample. Demographic characteristics of the individual samples can be found in Jason et al. [20]. Of the initial sample (N = 1,269), 55 participants were removed due to exclusionary medical or psychiatric conditions, lifelong fatigue, or not having a diagnosis of ME/CFS. Additionally, four participants were removed from subsequent analyses due to insufficient data, resulting in a sample of 1,210 participants.

Given that between 90% and 100% of ME/CFS patients endorse ‘core’ symptoms, such as prolonged fatigue, PEM, neurocognitive problems, and unrefreshing sleep [29], such symptoms would theoretically constitute the ME/CFS ‘supertype’ (i.e. an entity that contains attributes that are common to all subtypes).

While all individuals in our sample had a diagnosis of ME/CFS and were experiencing core symptoms of the illness (e.g. PEM),

 

[Dolphin]

Lastly, is there a quick and concise summary of each subgroup?

The symptom profiles and class proportions for the six-class solution are displayed in Table 3. Class 1 (13.6%) was characterized by a high probability (i.e. above 0.50) of endorsing all twelve symptoms. Class 2 (18.1%) was likely to only endorse symptoms related to gastro-intestinal distress (irritable bowel problems, bloating, and stomach pain). Class 3 (11.7%) was likely to endorse symptoms related to gastro-intestinal distress and circulatory impairment. Class 4 (11.7%) was likely to endorse only circulatory impairment symptoms (chills/shivers, feeling hot/cold for no reason, and cold limbs). The smallest class, Class 5 (10.3%), was likely to endorse circulatory impairment and OI symptoms (feeling hot/ cold for no reason, feeling unsteady on feet, dizziness/fainting, shortness of breath, and irregular heartbeats). The largest class, Class 6 (34.6%), was unlikely to endorse any of the twelve symptoms.

 

[arewenearlythereyet]

I wouldn't dream of suggesting excluding it from criteria as a very commonly experienced disabling symptom in ME that can help with diagnosis. I am just suggesting that it not be mandatory for ME to be diagnosed, at least until we have clearer tests for cognitive dysfunction and clearer tests for ME itself. I would put it in the same group with pain and orthostatic intolerance - very common symptoms of ME, but not mandatory.

But it's not up to me.

But there is no test for any of it? You can’t test PEM for example even though it’s diagnostic based on patient accounts. So why not cognitive problems alongside muscle fatiguability and PEM?

77% seems quite high to me ?

I don’t suppose it matters because it’s not up to me either

 

[Dolphin]

I think the best criteria may be by obtained by summing scores of symptoms, including severity and frequency.

But if one wants required symptoms, after postexertional malaise, cognitive symptoms and unrefreshing sleep show up in the highest percentage of patients from what I have seen, usually in the 90s%.

 

[Dolphin]

I used to think recovery of muscle strength might be useful as a required symptom.

But studies like this make be question that. Even the results of the repeat exercise tests are not that clear-cut in many ways.

http://www.meresearch.org.uk/our-research/completed-studies/upper-limb-muscle-function/

Recovery of upper limb muscle function in chronic fatigue syndrome with and without fibromyalgia

Authors
Ickmans K, Meeus M, De Kooning M, Lambrecht L, Nijs J

Institution
Pain in Motion Research Group, Department of Human Physiology and Physiotherapy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussel, Belgium

Background
Chronic fatigue syndrome (CFS) patients frequently complain of muscle fatigue and abnormally slow recovery, especially of the upper limb muscles during and after activities of daily living. Furthermore, disease heterogeneity has not yet been studied in relation to recovery of muscle function in CFS. Here, we examine recovery of upper limb muscle function from a fatiguing exercise in CFS patients with (CFS+FM) and without (CFS-only) comorbid fibromyalgia and compare their results with a matched inactive control group.

Design
In this case-control study, 18 CFS-only patients, 30 CFS+FM patients and 30 healthy inactive controls performed a fatiguing upper limb exercise test with subsequent recovery measures.

Results
There was no significant difference among the three groups for maximal handgrip strength of the non-dominant hand. A significant worse recovery of upper limb muscle function was found in the CFS+FM, but not in de CFS-only group compared with the controls (P<0.05).

Conclusions
This study reveals, for the first time, delayed recovery of upper limb muscle function in CFS+FM, but not in CFS-only patients. The results underline that CFS is a heterogeneous disorder suggesting that reducing the heterogeneity of the disorder in future research is important to make progress towards a better understanding and uncovering of mechanisms regarding the nature of divers impairments in these patients.

Publication
Eur J Clin Invest 2014 Feb; 44(2): 153–9

 

[adambeyoncelowe]

View attachment 3992

Thanks. So the subgroups are entirely defined by 'secondary' symptoms and seem to divide as follows:

Class 1 - All or most secondary symptoms
Class 2 - GI
Class 3 - GI and circulatory problems
Class 4 - Circulatory problems
Class 5 - Circulatory problems and OI
Class 6 - no secondary symptoms

CCC and ICC seem to select for Class 1, but less well for other classes (which comprise ~60%).

It seems that, if Jason is right, a modified four-symptom criteria could be developed with optional secondary criteria to define subgroup.

 

[Dolphin]

Note that there were lots of other symptoms that were more common than the symptoms looked at but not as common as the “core” symptoms that were not included in the analysis. They might work better to form subgroups.

In a factor analysis of patient responses to the DSQ [20], four factors were the maximum number that could be stably extracted due to sample size, three of which contained core symptoms (termed ‘Cognitive Dysfunction,’ ‘PEM,’ and ‘Sleep Dysfunction’) and one of which contained non-core symptoms (termed ‘Autonomic, Neuroendocrine, and Immune Dysfunction’). However, a parallel analysis indicated the existence of additional factors, so an exploratory factor analysis (EFA) was conducted on the large number of items that loaded onto the heterogeneous Autonomic, Neuroendocrine, and Immune Dysfunction factor. This EFA resulted in a three-factor solution: ‘Circulatory/Neuroendocrine Impairment,’ ‘Orthostatic Intolerance (OI),’ and ‘Gastro-intestinal Distress.’ The 12 items that loaded adequately onto these factors were used in the LCA in the present study: chills/shivers, cold limbs, feeling hot/cold for no reason, low temperature, unsteady on feet, dizziness/fainting, shortness of breath, irregular heartbeats, chest pain, stomach pain, irritable bowel problems, and bloating. These items were selected for inclusion in the current study, as their factor loadings were indicative of good construct validity and they were endorsed by an adequate number of individuals in our sample (between 18.0% and 53.0%), suggesting that they had the potential to constitute clinically-relevant illness subtypes.

 

[Dolphin]

I think the best criteria may be by obtained by summing scores of symptoms, including severity and frequency.

The CDC empiric criteria (Reeves et al, 2005), an operationalisation of the Fukuda criteria, used this method.

"Finally, subjects reporting ≥ 4 symptoms and scoring ≥ 25 on the Symptom Inventory Case Definition Subscale were considered to have substantial accompanying symptoms."

"For this study, we used the Symptom Inventory Case Definition Score defined as the sum of the product of the frequency and intensity scores of the 8 CFS case defining symptoms [14]."

https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-3-19

So you had to have at least four out of the eight Fukuda criteria symptoms. Each symptom scored 0-16 based on how frequently people had it, and the severity of it.

The total required to be diagnosed was 25.
As I recall, they picked this number out of the air.

I think it would be interesting if other thresholds were looked at using a bigger set of symptoms. I find it disappointing that Leonard Jason and his team haven't done that.

 

[Trish]

To be honest I really don't see the point of this subgrouping process. Rearranging the deckchairs won't help any of us get better. Until we have some biomarkers that distinguish some of us from healthy controls and which can be matched to symptom patterns, it's all speculation.

 

[Jonathan Edwards]

To be honest I really don't see the point of this subgrouping process. Rearranging the deckchairs won't help any of us get better.

My thought is that trying to define subgroups in the abstract is never a very useful exercise. Subgrouping can be very useful but on the whole each scientific or clinical issue you want to tackle is likely to benefit from a different way of subgrouping. For instance it can be useful to divide diabetes into non-obese and obese, or into insulin resistant and non-insulin resistant. The divisions may work out mostly the same but for different questions either one or other way is the better way to subdivide.

I have not read this paper but I do not get the impression that the subdivision is tailored to any very specific question.

 

[Barry]

I remain to be convinced that cognitive symptoms should not be a requirement. It seems to weak to base this on one study. It would be interesting to see the particular wording. The studies I recall in recent years had a much higher rate of cognitive symptoms.

I think I remember some of our members here saying that they have the physical symptoms but not the cognitive ones, which surprised me, but I also found very interesting. One thought is that something like cancer, though at the top level can be thought of as the same disease, affects sufferers very differently in some ways according to which part(s) of the body it attacks. Could ME be something which although essentially the same disease mechanism, affects people differently according to which parts of the body it affects?

 

[AliceLily]

I'm not sure about whether cognitive symptoms should be a requirement for ME diagnosis as you suggest, @Dolphin.

Some of us have the rapid muscle fatigueability, pain, orthostatic intolerance, unrefreshing sleep, etc, and, most importantly, very clear PEM, but don't seem to have very noticeable brain fog except during PEM.

I think brain fog is possibly apt for some members because their cognitive symptoms are not as severe as others.
@Trish Thank goodness we have some MEs like you who don't get the brain symptoms as bad as other MEs. You write so well and we need good speakers and writers like you.

I find the term brain fog an understatement of what I have experienced. I've never liked describing my brain symptoms as brain fog. What happened to me at my mild ME onset was shocking. I had a major change in brain function. So severe that I could no longer study. I had to drop out. It's been constant without change these last 20 years. Something significant happened. Brain fog is far too trivial a way of describing this change for me.

Some of us get hit harder in some areas more than others. After reading about other MEs gut problems in ME I feel I got away much more lightly in this area even though my gut was bad in the severe years, still not as bad as others.

 

[Trish]

Thanks for sharing your experience @Rosie. I am sorry you and so many others have been so hard hit by severe cognitive problems. I feel very lucky to have only mild brain fog most of the time.

Edit to add. I think this highlights my concern about this particular study. Why set out to subgroup ME patients and leave out the core symptoms? There is huge variation in experience of these which may be central to subgrouping.