Decreased Oxygen Extraction during Cardiopulmonary exercise test in patients with CFS

[Marco]

Why call it psych then?

Indeed - why?

 

[Marco]

They were assessed using the DSM, by professionals who were either not aware of their ME/CFS diagnosis or not taking it into account. By that standard, physical symptoms are used to arrive at a psychiatric diagnosis. And since CCC/ICC patients will have more physical symptoms and disability than Fukuda patients, using the DSM would result in more psychiatric diagnosis for the CCC/ICC patients.

This is a flaw with the DSM as a diagnostic tool, and that study is not a reliable indication of increased actual psychiatric co-morbidity in CCC/ICC patients.

I agree but it also raises the circular argument of wishing to exclude those labelled with 'depression' who may have been diagnosed that way because they reported a number of physical symptoms that are interpreted as indicating depression.

 

[Gijs]

I believe that a low Vo2 is the result of a dysfunctional autonomic reflex, the small blood vessels to the muscles squeeze together so that there is less blood flow. This reaction in combination with a low blood volume accounts for this phenomenon. There is a physical abnormal stress response in ME patients physical and mental effort. There is a kind of constant overdrive (like we are running all day). The body can, for some reason, not more relaxed. Relaxing is 'dangerous'. According our brain. This is the essence of the disease ME.

 

[Valentijn]

I agree but it also raises the circular argument of wishing to exclude those labelled with 'depression' who may have been diagnosed that way because they reported a number of physical symptoms that are interpreted as indicating depression.

Easy solution - they can stop trying to be clever bastards by "tricking" patients into revealing their supposed depression. This can be done by stopping the diagnosis of depression based on physical symptoms.

Depressed patients presumably experience numerous symptoms which are not at all physical. Hence there shouldn't be any problem in diagnosing them based on psychological symptoms instead of physical symptoms.

 

[Marco]

@Marco,

Sudden onset is a standard criterion for epidemiological investigation, even if there are cases without such evidence. There is no question we have patients available who really went from bouncing back from common viral infections to remaining in post-viral fatigue for an indefinite period. What changes in these cases?

The problem is not "contamination" of a cohort, it is dilution of any evidence which might make it possible to isolate causes. Remember that the number of cases of major depression is much larger than those meeting criteria based on more specific definitions of ME/CFS. For comparison, consider how little research on "cancer" was able to do when all cases were lumped together. For purposes of determining disability, you may not care about these distinctions, only the endpoint of the pathology. For research on etiology, the distinctions are literally vital.

There are also cases of patients that tolerated severe psychological stressors repeatedly and bounced back and then didn't. This pattern isn't unique to an apparent viral onset.

Not that I'm saying its not worth doing but a problem with this approach is that it assumes that a viral onset sub-group will itself be heterogenous. There's no a priori reason to assume this is the case.

My personal preference would be to comprehensively analyse dysfunction in each individual and then if necessary group them on the basis of empirical findings.

I wrote a piece some time ago describing a large study of childhood CFS patients who, inter alia, were objectively tested for cognitive function using event related potentials. The group comparisons showed no significant differences compared to controls but when the individual results were compared a minority of patients were statistically abnormal. The kicker was that two sub-groups could be described with abnormal results that were in opposite directions. These opposites cancelled each other out in the group comparisons.

There well be value in sub-grouping but on what basis?

 

[anciendaze]

@Marco, I think you meant "assumes that a viral-onset subgroup will itself be homogeneous."

The point is not that anyone knows there is a viral etiology, it is that something changes during an episode of viral illness in a substantial subset of patients. Whatever changes we need to find out what it is.

As for detailed investigation of individual cases, that would be the ultimate case of distinguishing differences between subgroups. Unfortunately, we have clear evidence that this simply will not happen for any of us who are not millionaires able to pay specialists from our own pockets. I am equally concerned as you about getting time histories of response to various challenges, which would indicate subtle differences in physiological variables not shown by averages. For all the numbers shown in this work, there is one simple measurement I have found very useful which is missing, heart rate recovery time following exercise. Heart rate variability also should be investigated, instead of assuming it is random. From things you have said I suspect you also differ from healthy controls in this respect.

What I'm objecting to here are a priori assumptions that the only significant symptom is fatigue, as defined in various sets of diagnostic criteria not suited to this illness. Failure to distinguish a subset with the clear physiological marker of PEM or PENE in a 2-day CPET is a great way to avoid recognizing that some of these patients have quite a different problem from most people with fatigue.

 

[Marco]

@Marco, I think you meant "assumes that a viral-onset subgroup will itself be homogeneous."

The point is not that anyone knows there is a viral etiology, it is that something changes during an episode of viral illness in a substantial subset of patients. Whatever changes we need to find out what it is.

As for detailed investigation of individual cases, that would be the ultimate case of distinguishing differences between subgroups. Unfortunately, we have clear evidence that this simply will not happen for any of us who are not millionaires able to pay specialists from our own pockets. I am equally concerned as you about getting time histories of response to various challenges, which would indicate subtle differences in physiological variables not shown by averages. For all the numbers shown in this work, there is one simple measurement I have found very useful which is missing, heart rate recovery time following exercise. Heart rate variability also should be investigated, instead of assuming it is random. From things you have said I suspect you also differ from healthy controls in this respect.

What I'm objecting to here are a priori assumptions that the only significant symptom is fatigue, as defined in various sets of diagnostic criteria not suited to this illness. Failure to distinguish a subset with the clear physiological marker of PEM or PENE in a 2-day CPET is a great way to avoid recognizing that some of these patients have quite a different problem from most people with fatigue.

Yes - sorry I was typing 'on the run'.

Indeed - what the 'Dubbo' studies tell us is that only a minority of people develop ME/CFS and that the speciific pathogen is irrelevant. What that then implies is that the problem is not a/the virus but the host response which has not been specified. This then opens up the possibility that any 'stressor' might evoke the same response which implies that viral onset cases are 'nothing special'. This negates the rationale for treating allegedly viral onset patients as a special case.

I agree that 'fatigue' is so ubiquitous and multidimensional as to be meaningless. But lets take PEM and PENE. These are just words - descriptions of reported exacerbation of symptoms with no objective underpinning. As I've related before the effect of physical of mental over-exertion is to turn me from a pretty fully functional person to losing the ability to walk, talk think etc - total meltdown. All very dramatic but nothing I can point to that says 'organic' as opposed to another form of words (such as conversion disorder) that also lacks any objective underpinning.

I fear we've been too uncritical of the supposed ME/CFS 'experts' to date who talk about PEM/PENE etc without providing any objective evidence for its existence.

This study appears to suggest a physiological deficit in oxygen uptake during exercise although the reason is still unknown. Yet we are now debating whether or not the inclusion criteria were valid?

I say - bank this one and move forward. I wouldn't expect the psychosocial crowd would dismiss a positive result because they didn't agree with the diagnostic criteria - just the opposite in fact.

 

[MeSci]

I fear we've been too uncritical of the supposed ME/CFS 'experts' to date who talk about PEM/PENE etc without providing any objective evidence for its existence.

Don't you think the study discussed in this thread provides objective evidence?

 

[Marco]

Don't you think the study discussed in this thread provides objective evidence?

Yes - which is why I queried why we were arguing over whether or not the Fukuda criteria were adequate or not.

 

[SOC]

Where to start?

As far as I'm aware I don't have immune dysfunction or at least no-one has ever shown me objective evidence that I do.

That begs the question of whether you have been adequately tested. For example, have you been tested for NK cell number and function, CD8+ count, IgG and IgM levels? And that's just the beginning.

The ICC requires immunological impairment:

The individual must demonstrate immunological impairment by meeting a total of at least three symptoms from three of these five categories:
1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion
2. Susceptibility to viral infections with prolonged recovery periods
3. Gastointestinal tract
4. Genitoruinary
5. Sensitivities to food, medications, odours or chemicals

Depending on how the questions are asked and interpreted I could easily meet both the CCC and ICC criteria but not Fukuda. Let's just say if I was asked the simple question - particularly in the early years - have you suffered from fatigue over the last 6 months - I'd have answered no - although I did have exercise intolerance and POTS plus other symptoms required by the 'better' criteria.

PENE is not exercise intolerance. Exercise intolerance is a symptom of a number of different diseases. POTS by itself, for example, can result in exercise intolerance without the other characteristic features of PENE. PENE, is described in the ICC as follows:

This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.

“Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
3. Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.
4. Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.”

[my bolding]

Only point 5 is the above list is similar to exercise intolerance. So exercise intolerance may be a part of PENE, but it is not equivalent to PENE.

Its also not clear at this point that pysch issues are not an organic part of ME (emotional lability as per Ramsey ME anyone). I accept that some and even many may not have them. I wouldn't expect everyone to be affected in the same way even if the problem is primarily neurological. I don't and never have had tender lymph nodes but I don't deny that others might.

So far, our experts have not included psychological issues as part of the CCC or ICC definition of ME/CFS. That's good enough for me for the moment. The last I remember reading was that depression is no higher in PWME than in the general population. So of course some PWME have depression and anxiety and even other psychological disorders. ME certainly doesn't protect us from such conditions.

Emotional lability is not a psychological disorder. It is an established neurological disorder not treatable by psychotherapy.

What exactly is 'clear organic illness'. Isn't it 'the point' that we don't have any objective markers of organic disease ...

No, that hasn't been 'the point' for a number of years now. There is no single biomarker that absolutely selects people with ME/CFS from those without. That doesn't mean there aren't plenty of objective markers of organic illness.

...and what exactly is PEM or PENE and how is it measured?

See above. In addition, appears the 2-day CPET is giving clear indications of measurable energy production dysfunction distinct from exercise intolerance.

Making a distinction between 'idiopathic' fatigue and ME, ME/CFS or CFS is an entirely arbitrary one at present as is a 'psychiatric' diagnosis.

No. If you read the CCC and the ICC, you can see clearly how the distinction between idiopathic fatigue and ME/CFS is made.

Let's face it MS used to be considered a 'clear psych issue'.

Yes, and that was incorrect. I'm not sure what your point is here.

If you wish to make a distinction between 'CFS' and Myalgic Encephalomyelitis (which I do have listed on my medical records BTW) then I'm afraid the only cohort who could logically qualify for a diagnosis of Ramsey ME are those who were hospitalised at the Royal Free at the time. Extending this diagnosis to anyone else is pure conjecture.

I don't try to make that distinction at this point. In my country the illness we have is called "CFS". That's the terminology/coding we're stuck with, fair or not, correct or not. That's why researchers in this country use that name for the illness in their research papers. We don't have to like it, but it's a reality we have to deal with.

I don't try to make everyone fit into the Ramsey ME diagnosis. Research has progressed since Ramsey's time (and I think he would have embraced the biomedical research that has happened since he was working). The CCC and/or the ICC are the best definitions we have based on what is currently known about the physical characteristics of the disease.

Don't call it ME or CFS or ME/CFS if you don't want to. The illness I (and most people here) am talking about is defined by either the CCC or the ICC. For convenience, the research community has temporarily settled on the name ME/CFS (or sometimes ME) for that illness. I'll use the name the top clinicians and researchers are using until we can get a better name. Whatever we call it, psychological issues are not a required part of either of those definitions.

 

[SOC]

We've gone pretty far OT here. Anyone else agree that we should split this thread to keep discussion of the paper clean?

 

[Marco]

That begs the question of whether you have been adequately tested. For example, have you been tested for NK cell number and function, CD8+ count, IgG and IgM levels? And that's just the beginning.

The ICC requires immunological impairment:

No I haven't been tested as under the UK NHS you count yourself lucky if you manage to have your blood pressure tested. The list of 'immune' symptoms are entirely subjective and not all likely to be immune mediated e.g. gastrointestinal tract, genitoruinary?

PENE is not exercise intolerance. Exercise intolerance is a symptom of a number of different diseases. POTS by itself, for example, can result in exercise intolerance without the other characteristic features of PENE. PENE, is described in the ICC as follows:

The reason I didn't claim to suffer from PEM/PENE is that neither has been objectively described. Following exercise (or other stressor) I lose the ability to walk, talk, think or otherwise function and these effects in the past have lasted between a matter of hours up to several months. This reaction would appear to fit the description of PEM/PENE but like those terms its merely words, dramatic though they may sound. I can't point to any physical abnormality causing this reaction and you could just as easily use another form of words with no objective support like 'conversion disorder' to describe these symptoms.

Now if you could consistently show that exercise results in abnormally low oxygen uptake (as this study suggest) and is invariably followed by a massively disproportionate increase in for example purinergic signalling (as per the Lights) then you may be getting somewhere in describing an objectively measurable phenomenon that is more than just words.

I should also add that PEM has also been described in Gulf War Illness and Post Concussion Syndrome so like exercise intolerance its not unique to ME/CFS.

So far, our experts have not included psychological issues as part of the CCC or ICC definition of ME/CFS. That's good enough for me for the moment. The last I remember reading was that depression is no higher in PWME than in the general population. So of course some PWME have depression and anxiety and even other psychological disorders. ME certainly doesn't protect us from such conditions.

I'm not surprised 'psychological' issues are excluded given the paranoia we seem to have over even mentioning them. Perhaps if we stopped treating 'depression' and 'anxiety' as conditions and started treating them as symptoms then we might have less angst over whether they should be included of excluded. If depression is no higher in PWME compared to the general population that would be a surprising finding indeed for a chronic illness as depression and anxiety are general higher in most organic illnesses (40% or so higher in diabetes) and in the autoimmune condition stiff person syndrome high levels of anxiety precede physical symptoms - i.e. it results from the underlying pathology and not just as a reaction to ongoing disability.

Emotional lability is not a psychological disorder. It is an established neurological disorder not treatable by psychotherapy.

As far as I'm aware all emotional lability means is emotions that are prone to rapid change and says nothing as to whether it is psychological or neurological. In fact the pyschologist Hans Eysenck described emotional lability as characteristic of those scoring highly on the neuroticism scale of his EPQ personality questionnnaire.

There is no single biomarker that absolutely selects people with ME/CFS from those without. That doesn't mean there aren't plenty of objective markers of organic illness.

Like what? The only consistent immune findings are elevated oxidative stress, low grade systemic inflammation and reduced NK cytotoxicity. The former are common in many conditions including depression and reduced NK cytotoxicity is associated with oxidative stress in type II diabetes and renal failure. Autonomic dysfunction is a promising consistent finding especially as it may be treatable but even then it isn't restricted to 'organic' illnesses.

Maybe I need more convincing than most people but I'd prefer that our 'experts' sharpened up and are able to back it up with hard objective and replicated data before they come out with definitive statements of what is or isn't present or required.

 

[MeSci]

No I haven't been tested as under the UK NHS you count yourself lucky if you manage to have your blood pressure tested.

It's true that UK GPs won't do a lot of the tests we would find useful, but I have found that bp checks are standard and frequent.

I'm not surprised 'psychological' issues are excluded given the paranoia we seem to have over even mentioning them. Perhaps if we stopped treating 'depression' and 'anxiety' as conditions and started treating them as symptoms then we might have less angst over whether they should be included of excluded. If depression is no higher in PWME compared to the general population that would be a surprising finding indeed for a chronic illness as depression and anxiety are general higher in most organic illnesses (40% or so higher in diabetes) and in the autoimmune condition stiff person syndrome high levels of anxiety precede physical symptoms - i.e. it results from the underlying pathology and not just as a reaction to ongoing disability.

I think it's important not to conflate anxiety with depression. Anxiety does indeed seem to be common in (and preceding) ME, and several of us have found that dietary change and supplements make a big difference to this. I saw a recent post in which a physiological process was described whereby dopamine is converted to noradrenaline, which I would guess could account for anxiety and 'adrenaline rushes'.

The reported lack of depression compared to other illnesses doesn't really surprise me. People with ME do appear to be unusually highly-motivated on average. I don't know whether this is due to genetic traits or something else.

The only consistent immune findings are elevated oxidative stress, low grade systemic inflammation and reduced NK cytotoxicity. The former are common in many conditions including depression and reduced NK cytotoxicity is associated with oxidative stress in type II diabetes and renal failure. Autonomic dysfunction is a promising consistent finding especially as it may be treatable but even then it isn't restricted to 'organic' illnesses.

Although possibly not consistent (maybe due to poor subject selection), I think that several cytokine abnormalities have been found, e.g. IL-6? Also differences in immunoglobulins. Also higher levels of autoantibodies than the general population.

 

[anciendaze]

It's a little difficult to produce "hard objective and replicated data" when alleged replicators insist on testing different patients using different diagnostic criteria.

Added: in writing the above, I missed the most common response, "we can ignore it for you wholesale". If no one even attempts to replicate you can be sure no one will succeed.

The whole issue of research on this problem is that conventional medicine has been shoving patients into a "head case" wastebasket for a long time. This disease didn't start with the name. I can easily believe that if you repeat the same tests conventionally used, and interpret results the same way, you will find the same thing as before. Technology has however moved on.

It is no trick at all to show that patients with organic diseases are regularly placed in mental wards. One problem we face is that once this label is applied doctors stop paying attention to anything the patient tells them, and don't run even routine exams carefully if they can avoid them. (Would you believe a glass eye being recorded as healthy?) It is also easy to show that patients with mental illness experience shorter life expectancy by something like 10 years. This is comparable to diseases like cancer.

It is something less than paranoia for people without prominent symptoms of mental illness to vigorously resist being subjected to a diagnosis which will have the effect of removing their civil rights and shortening their lives.

 

[Marco]

I think it's important not to conflate anxiety with depression. Anxiety does indeed seem to be common in (and preceding) ME, and several of us have found that dietary change and supplements make a big difference to this. I saw a recent post in which a physiological process was described whereby dopamine is converted to noradrenaline, which I would guess could account for anxiety and 'adrenaline rushes'.

The reported lack of depression compared to other illnesses doesn't really surprise me. People with ME do appear to be unusually highly-motivated on average. I don't know whether this is due to genetic traits or something else

I wasn't intending to conflate them but both are frequently reported symptoms.

If people with ME 'appear to be unusually highly-motivated' (which I suspect may just reflect the self-selecting mix found on forums such as this) then surely this would tend to support theories of 'personality as risk factors' rather than something as essentially random as viral onset. Unless our allegedly dodgy immune system also makes us unusually highly motivated?

Although possibly not consistent (maybe due to poor subject selection), I think that several cytokine abnormalities have been found, e.g. IL-6? Also differences in immunoglobulins. Also higher levels of autoantibodies than the general population.

When I was referring to systemic low grade inflammation (as a shorthand) I was referring to the PICs IL1b, IL6 and TNF-a. If immunoglobulins or autoantibodies are elevated they haven't been found consistently enough to be reported as consistent in recent reviews.

 

[Marco]

It is something less than paranoia for people without prominent symptoms of mental illness to vigorously resist being subjected to a diagnosis which will have the effect of removing their civil rights and shortening their lives.

With the greatest respect the issue was whether or not patients with a 'co-morbid' diagnosis of anxiety or depression or patients with these symptoms should be excluded from research cohorts.

Given that both symptoms are increasingly recognised as resulting from neuroinflammation 'head case' may well be an appropriate description but not one to be feared.

 

[MeSci]

If people with ME 'appear to be unusually highly-motivated' (which I suspect may just reflect the self-selecting mix found on forums such as this) then surely this would tend to support theories of 'personality as risk factors' rather than something as essentially random as viral onset. Unless our allegedly dodgy immune system also makes us unusually highly motivated?

I don't think we have enough evidence to say whether something (genetic? environmental?) predisposing us to be highly motivated might also be a risk factor for various possible causal factors, such as leaky gut, immune system abnormalities, etc., etc. For example, a gene, or combination of genes, is often involved in a range of different physiological characteristics, and I see no reason why these can't include effects on personality. The high motivation could well be related to the anxiety, with something like excess noradrenaline driving both.

 

[anciendaze]

With the greatest respect the issue was whether or not patients with a 'co-morbid' diagnosis of anxiety or depression or patients with these symptoms should be excluded from research cohorts.

Given that both symptoms are increasingly recognised as resulting from neuroinflammation 'head case' may well be an appropriate description but not one to be feared.

While I also suspect many cases of mental illness have organic causes currently being overlooked, I do not find the history of the subject at all reassuring. I also think it would be better for research purposes concerning organic disease to work with cases which do not present such complications. I have seen cases where people with illness doctors did not understand were committed (sectioned). In some cases the diagnosis was corrected at autopsy.

I could launch an even longer digression from topic here on the reasons for medical commitment. I've had dealings with some cases of severe mental illness, and I acknowledge the necessity of sometimes committing patients involuntarily when they present a serious danger to others, or an immediate threat to themselves. (If you plan to heave massive objects through the windows of people you don't like, you won't get any support from me.) I've also acted to prevent suicide in more than one instance.

What I think represents an entirely different rationale is involuntary treatment of people who present no direct threat to others or themselves. Arguments that they are going to cost society money, or that failure to exercise when someone else thinks they should be capable presents a threat to their own lives are extremely dangerous precedents which could apply to just about any disliked group. Such actions do take place.

If people reading this want it, I will compose a blog post on the subject. I think I've gone far enough on this thread.

 

[Ronnie]

The reported lack of depression compared to other illnesses doesn't really surprise me. People with ME do appear to be unusually highly-motivated on average. I don't know whether this is due to genetic traits or something else.

This thought just hit me. When my activity amount (physical and/or mental) goes above the limit for getting PENE, at I first feel very tired. If I continue pushing I get an energy boost and start feeling better. At the same time my thought processes are affected, like for example becoming overly optimistic about what activities I am able to execute without getting PENE. I have been thinking that these effects may be caused by adrenaline being released, primarily to make more energy available, but also having other (mental) effects. Maybe something like this could explain any lack of depression compared to other illnesses?