A Novel Nutriceutical Treatment of ME/CFS, 2017, Comhaire

[alex3619]

I'm sorry about that, I would appear to be unable to communicate what seems to me to be a very simple thing.

The problem is that fatigue is not a simple thing, and its not precise. Its like saying pain, or being sick, or depression. Its a general term. We do know that fatigue perception is in part based upon acid sensors in the blood vessels. The Lights did research on this. So if we push and our lactate goes up we will feel increased fatigue. This is a surrogate for the actual problem, the energy problems that lead to lactate in the first place. Most cases in the literature are from oxygen supply issues. This is what happens during exercise, and from some kinds of vascular problems and poisoning. Its not clear that our problem is primarily about oxygen, its more about mitochondrial regulation.

So everyone can feel fatigue, but the closest sensation to our problem is when hitting the wall during intense exercise, that point when you cannot produce more energy but will shortly get your second wind as the body switches primary energy sources. We live at that wall, and for severe patients and worse I think its 100% of us live there 100% of the time, though that is speculation. I would love a formal test showing this, or disproving it.

We also know that fatigue can be produced from cytokines and other immune factors. That may play a role too.

 

[Bill]

You can push through fatigue. You cannot push through energy limitations.

I don't mean to seem obstreperous, but that does not comport with my experience of ME/CFS related fatigue for the past 34 years.

Fatigue is the feeling one has from having a lack of energy. Trying to push through bad fatigue sets one up to crash (PEM), where the fatigue (and other symptoms of the syndrome) are exacerbated further.

Fatigue and the brain-fog that goes with are the #1 symptoms in my expression of this illness by a wide measure.

Bill

 

[adambeyoncelowe]

I don't mean to seem obstreperous, but that does not comport with my experience of ME/CFS related fatigue for the past 34 years.

Fatigue is the feeling one has from having a lack of energy. Trying to push through bad fatigue sets one up to crash (PEM), where the fatigue (and other symptoms of the syndrome) are exacerbated further.

Fatigue and the brain-fog that goes with are the #1 symptoms in my expression of this illness by a wide measure.

Bill

It's not pushing past the fatigue, per se, which causes PEM--it's pushing past your energy envelope. Fatigue is just the sensation or awareness of having a small energy envelope. Your fatigue levels might feel lower or higher based on, say, if you've had a cup of tea. But your energy envelope is always the same (well, mostly--deterioration and improvement happen over the long term). I can temporarily improve my fatigue, but I can't improve my energy envelope.

 

[alex3619]

Fatigue and the brain-fog that goes with are the #1 symptoms in my expression of this illness by a wide measure.

My point is that perceived symptoms and underlying biochemistry are not the same. The type of fatigue I often get that leads to PEM if I push through it is different from fatigue I get from other things. Fatigue is not a monolithic entity, and its more a cultural description of extremely complex processes that science has not figured out yet.

I myself use fatigue as an indicator. Its often a misleading indicator, as I can crash from activity even when I do not feel fatigue. In fact I consider that the most insidious form. When I am very fatigued I know to hold back, rest, and pace more. When I feel fine its very easy to think I can do a bit more. Sometimes I can, and sometimes I pay for it. We need to understand those underlying biochemical processes a lot more than we do.

 

[Bill]

The problem is that fatigue is not a simple thing, and its not precise. Its like saying pain, or being sick, or depression. Its a general term. We do know that fatigue perception is in part based upon acid sensors in the blood vessels. The Lights did research on this. So if we push and our lactate goes up we will feel increased fatigue. This is a surrogate for the actual problem, the energy problems that lead to lactate in the first place. Most cases in the literature are from oxygen supply issues. This is what happens during exercise, and from some kinds of vascular problems and poisoning. Its not clear that our problem is primarily about oxygen, its more about mitochondrial regulation.

So everyone can feel fatigue, but the closest sensation to our problem is when hitting the wall during intense exercise, that point when you cannot produce more energy but will shortly get your second wind as the body switches primary energy sources. We live at that wall, and for severe patients and worse I think its 100% of us live there 100% of the time, though that is speculation. I would love a formal test showing this, or disproving it.

We also know that fatigue can be produced from cytokines and other immune factors. That may play a role too.

Sorry, but (again) I find these distinctions without differences. If some mechanism in the body interferes with our energy production (which is likely the case) we don't think "my mitochondria seem sluggish." What we experience is fatigue.

I agree entirely that there must be root causes of this lack of energy problem, but they are inextricably linked.

Bill

 

[Bill]

My point is that perceived symptoms and underlying biochemistry are not the same. The type of fatigue I often get that leads to PEM if I push through it is different from fatigue I get from other things. Fatigue is not a monolithic entity, and its more a cultural description of extremely complex processes that science has not figured out yet.

I myself use fatigue as an indicator. Its often a misleading indicator, as I can crash from activity even when I do not feel fatigue. In fact I consider that the most insidious form. When I am very fatigued I know to hold back, rest, and pace more. When I feel fine its very easy to think I can do a bit more. Sometimes I can, and sometimes I pay for it. We need to understand those underlying biochemical processes a lot more than we do.

We cross posted. We agree entirely that the symptom of a lack of energy (fatigue) and the root cause of the fatigue are not precisely the same thing. Granted. But as we really don't know the mechanism, what we experience as a result of this lack of energy is fatigue.

I think we get pretty good at differentiating between how much energy we have based on our fatigue levels, learning how far we can push before we risk PEM (which further compounds profound fatigue and energy issues). I find fatigue is a really good indicator.

Can other factors set up PEM? Sure. In earlier years, especially, exposure to certain chemicals could put me to bed with a bad crash (when I would have an extreme lack of energy and crippling fatigue).

We share the opinion that we need to understand those underlying biochemical processes that set up fatigue/PEM than we do now.

Bill

 

[Bill]

It's not pushing past the fatigue, per se, which causes PEM--it's pushing past your energy envelope. Fatigue is just the sensation or awareness of having a small energy envelope. Your fatigue levels might feel lower or higher based on, say, if you've had a cup of tea. But your energy envelope is always the same (well, mostly--deterioration and improvement happen over the long term). I can temporarily improve my fatigue, but I can't improve my energy envelope.

Seems like an argument over semantics. Being aware that one has a "small energy envelop" through the body's expression of fatigue is the most sophisticated guide we have day-to-day to gauge/modify our activity levels to help avoid even worse fatigue as a result of a PEM crash.

I don't think it is established that we can't increase our energy envelops. I'm quite hopeful that is not the case, otherwise, why bother trying to find the mechanisms?

I'm interested in learning the root causes so we can hopefully reduce the life-limiting fatigue.

Bill

 

[Mij]

I think we get pretty good at differentiating between how much energy we have based on our fatigue levels, learning how far we can push before we risk PEM (which further compounds profound fatigue and energy issues). I find fatigue is a really good indicator.

You are fortunate to have this fatigue indicator as a warning. But for some of us there is no fatigue 'indicator'. I have only my experience of 27 years to rely on and how much I can do before I reach PEM. I feel almost normal on some days when I start out (no fatigue) and can even run for 30-40 minutes but I know without a doubt that the next day will almost be death.

 

[Bill]

You are fortunate to have this fatigue indicator as a warning. But for some of us there is no fatigue 'indicator'. I have only my experience of 27 years to rely on and how much I can do before I reach PEM. I feel almost normal on some days when I start out (no fatigue) and can even run for 30-40 minutes but I know without a doubt that the next day will almost be death.

In turn, you are fortunate to have days where you don't experience fatigue. Out of my last 12,401 (or so) days with CFS, I've had less than a hand-full where the fatigue was far enough in the background that I felt nearly-normal. I had a couple of those days recently. I nearly wept with joy. Those rare days give me hope I (and we) are not eternally broken.

Best,

Bill

 

[Woolie]

I suspect that the collection of complaints normally earning the term MECFS is almost certainly heterogeneous. To me, there seem to be at least to major subgroups. One seems to fit an "energy depletion" model. These people feel they have limited energy most of the time, and once they use up what's in their "battery", they crash. These folks feel tired most or all of the time. The main thing that limits them is current levels of fatigue.

The other group seems to fit an overactive immune system model. These people get a lots of malaise (flu-feeling), burning glands, etc. For these people, symptoms are variable from day to day, and its quite possible to feel presently okay to do something, but "know" that if you did, you would pay for it dearly by bringing on a major crash the next day.

I'm in the second category.

I don't think any of us should be calling anyone else "fortunate". I have days with very little of what I would describe as fatigue (just a hot sick feeling, but not that feeling of heaviness that is the core of fatigue). That might sound lucky to some. But during my flares, I can't lift my head from the bed. My whole body and head is burning. And that can go on for weeks.

It may turn out that the disease mechanism in these two groups is different, or it could be the same, we just don't know yet. Also these two "groups" might not be as distinct as I make out, they could be ends on a continuum. All we know is that our symptomatology varies.

 

[Bill]

I suspect that the collection of complaints normally earning the term MECFS is almost certainly heterogeneous. To me, there seem to be at least to major subgroups. One seems to fit an "energy depletion" model. These people feel they have limited energy most of the time, and once they use up what's in their "battery", they crash. These folks feel tired most or all of the time. The main thing that limits them is current levels of fatigue.

The other group seems to fit an overactive immune system model. These people get a lots of malaise (flu-feeling), burning glands, etc. For these people, symptoms are variable from day to day, and its quite possible to feel presently okay to do something, but "know" that if you did, you would pay for it dearly by bringing on a major crash the next day.

I'm in the second category.

I don't think any of us should be calling anyone else "fortunate". I have days with very little of what I would describe as fatigue (just a hot sick feeling, but not that feeling of heaviness that is the core of fatigue). That might sound lucky to some. But during my flares, I can't lift my head from the bed. My whole body and head is burning. And that can go on for weeks.

It may turn out that the disease mechanism in these two groups is different, or it could be the same, we just don't know yet. Also these two "groups" might not be as distinct as I make out, they could be ends on a continuum. All we know is that our symptomatology varies.

Early in my disease, I suppose I fell into both these subtypes. Feverish symptoms were ever present initially. My glans were swollen, tender, and radiated pain. I'd soak my bed with drenching night-sweats, lights, sounds, and especially bad chemicals could put me into a severe crash. At the same time, the fatigue was incapacitating.

As time when by the second subtype symptoms largely dissipated. Not completely, and it took years. I had sore glans in my neck last year and I must admit being scared to death that I might be re-entering an active type 2 phase, but it passed.

Now I'm mostly limited by fatigue and brain-fog. However, it is still highly variable from day to day and there are trends up and down over time. Overdoing it is an ongoing danger, as I like to remain as active as I can.

The very few days out of the past 30 plus years where I've felt nearly-normal continue to give me hope.

Weird illness.

Bill

 

[Alvin]

I suspect that the collection of complaints normally earning the term MECFS is almost certainly heterogeneous. To me, there seem to be at least to major subgroups. One seems to fit an "energy depletion" model. These people feel they have limited energy most of the time, and once they use up what's in their "battery", they crash. These folks feel tired most or all of the time. The main thing that limits them is current levels of fatigue.

The other group seems to fit an overactive immune system model. These people get a lots of malaise (flu-feeling), burning glands, etc. For these people, symptoms are variable from day to day, and its quite possible to feel presently okay to do something, but "know" that if you did, you would pay for it dearly by bringing on a major crash the next day.

I've had similar thoughts, only time will tell.

 

[alex3619]

To me, there seem to be at least to major subgroups.

This issue has come up with the biochemistry many times. There seems to be about a one-third/two-third split. This means they are in different subgroups for one parameter. Until we know if this is the same split for all such parameters we cannot be sure of everything. I am hoping some of the deep biochemistry studies will show us what is what.

 

[alex3619]

The very few days out of the past 30 plus years where I've felt nearly-normal continue to give me hope.

Yes, those rare days indicate that whatever is going on is some kind of biochemical switch. If we can figure it out we might be able to switch it off permanently.

 

[Bill]

Yes, those rare days indicate that whatever is going on is some kind of biochemical switch. If we can figure it out we might be able to switch it off permanently.

I profoundly hope that is correct.

Bill

 

[Woolie]

This issue has come up with the biochemistry many times. There seems to be about a one-third/two-third split. This means they are in different subgroups for one parameter. Until we know if this is the same split for all such parameters we cannot be sure of everything. I am hoping some of the deep biochemistry studies will show us what is what.

Its a tricky predicament - how to study something when you don't know if its a homogeneous something or a heterogeneous something.

My own background is in neuropsychology, where we face this problem a lot. So two people who fit the diagnosis for "Broca's aphasia" can have entirely different profiles and different underlying brain damage. We have tackled this problem by using case series designs - so instead of averaging data across individuals within a group, we focus on variation across individuals, and whether its predicted by other factors (for example, do scores on a general knowledge test correlate negatively with degree of damage to the left temporal pole?). And we report each individual's data, never, ever, averages. Because of the fruit problem.

(The fruit problem: if you ask a question like "what is the average colour of fruit?", you will get a stupid answer, because you've averaged away all the important variation.)

Seems to me that's the approach you need to take whenever you study a "syndrome" which is primarily defined by its presenting features.

I have wondered if there's a way to apply it to biomedical studies of MECFS.

 

[chrisb]

I think that a major problem in describing the symptoms arises from the progression of the illness. I know the experts tell us it is not a progressive illness, but they in general make no attempt to follow the long term cases, and have a limited evidence base.

There would then arise questions about whether cases progress through different stages at the same rate,and whether intermediate stages might be omitted.

If you do not consider aetiology there is no way of knowing whether you are considering the same condition at different stages. Aetiology was one of the first ideas to go under the new approach.

 

[Woolie]

If you do not consider aetiology there is no way of knowing whether you are considering the same condition at different stages. Aetiology was one of the first ideas to go under the new approach.

Granted, but we're talking about when you don't know the aetiology yet, and you probably won't know it till you've got more evidence, but you might never find that evidence if you average away all the important variability.

 

[chrisb]

I think you have to start with what you know, look for common factors, and then ser if they are present in other groups. You never discover anything if your first step is to hugely expand the area of search.

 

[adambeyoncelowe]

Younger thinks there are three main subgroups: metabolic, viral (reactivating, persistent or just post-viral) and autoimmune/inflammatory. I don't know how correct he is, and we can't really debate it until he posts the results, but that seems to correlate to the varied results we've seen so far. Of course, it may be that we're seeing at least some patients misdiagnosed, and there may be a better description or diagnosis available for at least some of them.

Even in the early days, doctors were pretty sure there was a spectrum of illness, with epidemic neuromyasthenia at one end (more focused on fatigue) and benign myalgic encephalomyelitis at the other (with more neurological signs). There was a 1977 conference where they debated this ad nauseam and still couldn't agree on one term. Perhaps they were seeing the metabolic group at one end of the spectrum and the viral group on the other?

It's not helped, of course, that clinicians aren't always consistent in how they diagnose the illness. CFS clinics here keep talking mostly about 'chronic fatigue' and 'fatigue spectrum illnesses', which means they're only really diagnosing fatigue. I noticed it both on my table at NICE and at the local CFS clinic, where the specialist specifically mentioned the 'fatigue spectrum illnesses' to me. I think that many doctors in the UK are treating CFS as a wastebasket diagnosis rather than as a positive diagnosis. Not always, but enough that it's a problem.