Andy's attempt to create a reasonable descriptive model of ME.

[Saz94]

@Trish @Jonathan Edwards

On the topic of calories and BMR... I have found that my calorie need (for an ordinary day where I am not overexerting myself) increased when I developed ME, and increased when my ME increased with severity. So I need to eat a lot of calories in order to function at my best. But there is still a point at which eating extra calories will not give me any more extra energy and will just make me put on weight.

This seems to be the case for some Pwme, but only some.

 

[rvallee]

So I guess the question is why are Day 1 CPET results pretty normal?

How long is a CPET and how much energy does a typical run require? How many calories is it typical to spend?

Most importantly, how does it compare in terms of sustaining energy expenditure with light running all day, for days, chasing prey, which is something a healthy body is perfectly capable of doing?

There is an ultramarathon, in Australia I think, where participants jog for 3 straight days. Non-stop. This is of course peak human ability, but this is the ceiling we are working with. Most healthy people are capable of working 10-hour days of manual labor for years. They will be tired, even exhausted, from it but they can keep on doing it. This is way above the typical energy expenditure of what a CPET demands if mild ME patients can participate, the difference between walking to the corner store vs. a full marathon.

So likely the CPET is simply not sufficient to properly test. It can compare somewhat, but it's not a reliable test of real capacity. I look at going upstairs about the same way my healthy self would have looked at a 1h walk. The gap is enormous but we have simply never quantified accurately. It's easily a 90%+ drop for myself and this is the best case scenario, my "baseline".

 

[rvallee]

So I can sprint pretty fast for say approximately 40 meters but cannot go for a simple walk with my family during holidays. So it seems like an issue of endurance.

I think this is important. Fits my experience as well. Short-term energy expenditure is still available, my strength isn't much different. It just drops precipitously very quickly. Frankly a 20 minute walk seems more daunting than a 40-meter dash, although the payback would probably be similar.

It's like there are energy buffers that can be used readily but aren't refilled quickly enough to be used reliably. And when you exhaust that buffer something else kicks in that stops the short-term buffer from being filled and runs everything on some alternative low-power mode.

 

[Barry]

To me it always seems not just about how much energy is in reserve, but also very much about the rate at which the energy can be supplied. The faster you do something the faster the energy has to be made available to provide the power for it. Walking up a slope in 10 mins takes the same energy as walking up the same slope in 20 mins, but in the former case the energy has to be supplied twice as fast (ignoring air resistance ) - twice the power. If the energy cannot be supplied faster than the latter case, then you absolutely will not be able to get up the same slope faster than 20 mins, no matter what

If you put your foot to the floor in a car to overtake, then fuel (energy) flows faster into the engine to provide that extra power needed. If for some reason the energy cannot flow as fast as it should (e.g. the fuel pipe partly blocked), then no matter how hard you push on the pedal, the car is not going to accelerate as fast as it should.

I very much suspect it is about the rate of energy delivery - and maybe rate of energy replenishment - that is what counts. Maybe whatever limits the rate at which energy can be used, perhaps also limits the rate at which it can be replenished? Of course once the rate of energy flow is compromised, that might also have knock on effects regarding energy storage levels achieved ... which in turn might then impact energy delivery rates ... !!! It could all get rather incestuous.

 

[BruceInOz]

I very much suspect it is about the rate of energy delivery - and maybe rate of energy replenishment - that is what counts.

This certainly agrees with my experience.

I tend to have more problems cognitively than with muscles, so I can manage ok with medium walks on flat terrain. But as soon as the ground starts sloping up a little I must slow right down. If I slow down enough I can then keep going uphill.

So it very much feels like it's about power (i.e., rate at which energy is used) rather than energy for me.

 

[Barry]

If I slow down enough I can then keep going uphill.

So it very much feels like it's about power (i.e., rate at which energy is used) rather than energy for me.

Exactly. Same for my wife.

 

[Barry]

however there are reports from patients of declines despite avoiding overexertion to the best of their abilities.

A point to consider here I would think, is that the nearer a person's SEL drops towards their essential life support requirement, the harder it will become to not push beyond that limit. If it is getting more and more difficult to do the very basics (washing, going to the loo, etc), there will be an overwhelming temptation to maintain the dignities of life as long as possible. I suspect that will overrule any background awareness to not push so hard. But the effort of doing that may be contributing to whatever cumulative effect it is that makes people decline.

ETA: As I start to catch up with this thread, I realise "basal metabolic rate" is the terminology I should probably have used, where I said "essential life support requirement".

 

[Barry]

Personal note: I don't know if I'm alone or an exception in this regard, but what Andy has written better explains my situation than the word 'crash', which is often used in relation to PEM. 'Crash' makes it sound like it's a very abrupt mechanism. In my case, PEM isn't that sudden or dramatic, it's more like an excessive payback that is spread out over a period of a couple of days, usually more than a week. And if I try to push through it, I only make it worse.

Observing my wife, I get the feeling there are two sides of the same coin possibly in play. It's as if the mechanism (whatever it is) that obstructs the flow of energy to the muscles etc, might also play a part in obstructing the flow of energy when trying to recharge. Akin to a battery with a much higher internal resistance than it should normally have - it won't be able to dispense energy at a fast enough rate, but neither will it be able to recharge at a fast enough rate either. Discharging and recharging - in biological systems do these both share some common pathways?

 

[NelliePledge]

Yes @Barry i feel I have my battery on trickle charge while coming back from PEM.

 

[Barry]

Yes @Barry i feel I have my battery on trickle charge while coming back from PEM.

I suspect when this is all much better understood, that will not be far from the truth.

 

[Marky]

Some important questions i often think of..

1. Why do most ME-patients get PEM so much faster when e.g doing the same mental activities standing or sitting, compared to lying. What does this indicate in terms of disease mechanism.
2. How is it possible to exert yourselves into a permanent state of lower functioning, and what does that indicate in terms of disease mechanism?
3. A good nights sleep seemingly have no effect what so ever on energy levels (I actually feel almost the same not sleeping one night), and ME-patients often wake up more exhausted than they were going to bed. What may this indicate in terms of disease mechanism?
4. Having this little energy is catastrophic for the body, and in ancient times we would surely all be dead by now. What is stopping our bodies from functioning normally, as it always/normally works hard to meet energy demands? Is there a permanent lack of something, a permanent increase of something, or some kind of systemic dysfunction due to something else(e.g. signalling)?

 

[Saz94]

2. How is it possible to exert yourselves into a permanent state of lower functioning, and what does that indicate in terms of disease mechanism?

THIS, this is the most important question in my opinion.

It's the most bizarre medical thing that I've ever heard of, it seems to defy all 'standard' understanding.

It seems unbelievable to people.

Physically, there is at least some kind of precedent in terms of overtraining and injury and stuff like that. (I know these are completely different things to ME, but at least there's some level of understanding that people can be harmed through physical exertions)

But cognitively??? HOW is it possible that a person's cognitive function can be permanently worsened by a few days of cognitive overexertion?!?! It makes NO SENSE. And yet it happens.

We NEED to find an answer to this.

Honestly it's such a ridiculously awful and illogical disease pattern that it does sometimes make me wonder if it's a sort of curse imposed by supernatural forces, rather than a disease. (I know this is a completely unscientific statement, and I don't actually think that; I'm just saying how I feel sometimes.)

 

[Trish]

I've spent most of today trying to figure out how to illustrate graphically what I've been trying to say on this thread. And then more hours figuring out how to upload it here. This is the result. Of course it's illustrative, the numbers are invented, but reflect my experience.

The example is for a woman with mild to moderate ME compared with a healthy woman, both attempting GET based on trying to increase their activity in increments of 10% of their starting activity level (the bit above basal level).

Edit: I used a basal metabolism calculator for an average 40 year old woman and it came to 1400 calories. I worked on the basis of a healthy women being recommended a daily intake of 2000 calories (edit: and a female athlete in training about 4000 calories), and the woman with ME only being able to sustain half of what the healthy one is doing at the start.

 

[Barry]

A good nights sleep seemingly have no effect what so ever on energy levels

True for so many pwME. Is this also a clue that the recharging of energy is obstructed in some way, as well as the discharging (usage) of energy seems to be?

 

[Barry]

I've spent most of today trying to figure out how to illustrate graphically what I've been trying to say on this thread. And then more hours figuring out how to upload it here. This is the result. Of course it's illustrative, the numbers are invented, but reflect my experience.

The example is for a woman with mild to moderate ME compared with a healthy woman, both attempting GET based on trying to increase their activity in increments of 10% of their starting activity level (the bit above basal level).

Edit: I used a basal metabolism calculator for an average 40 year old woman and it came to 1400 calories. I worked on the basis of a healthy women being recommended a daily intake of 2000 calories (edit: and a female athlete in training about 4000 calories), and the woman with ME only being able to sustain half of what the healthy one is doing at the start.

View attachment 8243

First thoughts:

1. I presume the x-axis is "energy, in calories per day", the healthy-GET person using energy at a faster rate as the weeks go by.
2. Not suggesting you change your graph, but the x-axis must relate more to "energy usefully applied" in some way, because my wife's energy intake rate (i.e. food) is much the same as it always was, and her weight is not excessive and is fairly constant. So she takes in the calories of a normal person, but less of those calories get usefully applied than for a healthy person. So there is an energy-efficiency issue somewhere. Where does the 'unused' energy go? Does it go through the body as inadequately processed food? Or as excess heat? Do the muscles for some reason need more energy in than normal, for normal energy out? Or is the illness mechanism such that it "steals" some of the energy for its own nefarious purposes? Whatever it is, the laws of physics means some energy that gets taken in, is ending up where it's not meant to.
3. Although a complexity not for this graph, the thought occurs to me that a person's basal level may not be as simple and as flat as might seem. Because basal level is much more likely a range, spanning from a) Power (i.e. energy consumption rate) needed to keep your life functions going comfortably, when all is fairly OK, down to b) Power needed to just about stop you from dying - a brutal truth unfortunately.
4. The very severe doubtless live close to 1b.

 

[Trish]

Yes the vertical axis is energy expended in calories per day. It's a simplified model, with the healthy person doing GET steadily adding a bit more activity each week to the level of an athlete's training over 6 months, while the sick persons attempts at GET lead to repeated relapses. Of course it's over simplified. Basal level may well vary over time, and nobody sticks that strictly to an activity program.

 

[Barry]

Yes the vertical axis is energy expended in calories per day. It's a simplified model, with the healthy person doing GET steadily adding a bit more activity each week to the level of an athlete's training over 6 months, while the sick persons attempts at GET lead to repeated relapses. Of course it's over simplified. Basal level may well vary over time, and nobody sticks that strictly to an activity program.

Just to be clear @Trish, my comments were not criticism, far from it. Just observations.

 

[Ravn]

Sustainable Exertion Limit (SEL) - I like it!

The word exertion may need some definition though. Healthy people tend to interpret exertion as being the same as physical exercise such as jogging. Whereas we think of it more as any energy-demanding process (physical or cognitive activity, infection, sensory processing, etc.).

Thought experiment - an attempt at combining:

• @Andy's model
• the observation by several others in this thread that SEL is not fixed
• the observation that sometimes some level of overexertion is temporarily possible
• the observation that sometimes, after a major crash, our functioning is permanently reduced

I propose that there are THREE thresholds:

1) a SEL threshold - exceeding this does not cause PEM but it lowers all thresholds

2) a fully symptomatic PEM threshold (fsPEM), higher than SEL - exceeding this does cause PEM and lowers all thresholds

3) a critical point threshold (CP), higher than fsPEM - exceeding this does cause PEM and lowers all thresholds and permanently lowers 'baseline'

Example (the numbers are just for illustration, they don't correspond to any specific severity; the word recover in the example means recover to pre-PEM state, not to healthy):

Starting SEL=40 & fsPEM=60 & CP=90 ---> PwME exerts at 50. This doesn't cause PEM but it lowers SEL & fsPEM.

New SEL=33 & fsPEM=53 & CP=83 ---> PwME exerts at 50 again. This still doesn't cause PEM but it lowers SEL and PEM further.

New(2) SEL=26 & fsPEM=46 & CP=76 ---> PwME exerts at 50 again. This now causes PEM because it exceeds the new(2) fsPEM=46.

PwME's reaction to PEM, option 1:

PwME reduces exertion to 30, thinking that is safe because starting SEL was 40. But because 30 is higher than the current SEL (26) the PwME remains in PEM (for recovery from PEM exertion needs to be below SEL, not just below fsPEM). Thresholds lower further.
New SEL=19 & fsPEM=39 & CP=69 --> The downhill trend continues.

OR

PwME's reaction to PEM, option 2:

PwME reduces exertion to 20. This is lower than current SEL (26) so PwME begins to recover. Thresholds begin to rise again (but only after several days because PEM, once started, doesn't go away overnight).

Other scenarios:

Starting SEL=40 & fsPEM=60 & CP=90 ---> PwME exerts at 70. Leads to immediate PEM. Eventual recovery to Starting SEL=40.

OR

Starting SEL=40 & fsPEM=60 & CP=90 ---> PwME exerts at 100. Leads to immediate PEM. Eventual recovery only to Below Starting SEL=35.

Severity in this model could be varied by higher or lower starting thresholds as well as by the magnitude/speed by which thresholds go down after overexertion, or recover after rest.

NB: The graphic doesn't follow the above scenarios exactly but tries to combine the various options. A bit messy, I admit, but haven't got the energy to try again right now.
View attachment 8215

Refining my previous attempt (copied above for reference).

I think recovery, or lack thereof, needs to be factored into our model. Think 2-day CPET, unrefreshing sleep, muscle fatiguability, etc. All suggest that, whatever our starting ability when rested, we don't recover back to it at the speed we should, and sometimes we don't recover fully back to where we were.

This recovery deficit could explain the lack of sustainability in @Andys's concept of sustainable exertion limit.
And it could fit in with @Barry's concept of slow recharging/slow rate of energy delivery.
It could also fit @Trish's illustration of why we don't get fitter with GET.
If we define 'exertion' as any process that requires energy, it could also explain @Sarah94's observation that cognitive exertion can lead to PEM and deterioration.

Healthy people, as @Andy points out, also have an SEL, albeit a much higher one than us. When they exceed theirs, they also get exhausted and in extreme cases they even get ill as in Overtraining Syndrome. The big difference is in their recovery. Depending on the level of overexertion they may just need a short nap, a good night's sleep, or a reduction in their training programme to fully recover.

My new graph represents how a PwME may deteriorate over time by exceeding their SEL and not allowing enough time for recovery. Let me talk you through the graph:

The blue and red upright bars represent alternating exertion and rest periods respectively. Note that the red rest bars are not set to zero exertion. This is to capture our recovery deficits and the possibility that we actually use too much energy during 'rest'.

The lines represent limits or thresholds we cross at our peril.

Staying below the light-blue Recovery Threshold allows for recovery (up to the individual's personal maximum level, which may not be very high in ME).

Exertion above the recovery line but below the SEL line means a stable phase. That's illustrated by the first two blue bars at the left of the graph.

The next 5 exertion bars (blue) show the person going above their SEL. This results in symptoms like exhaustion (but not full PEM), similar to what a healthy person would experience after going beyond their SEL, only for us it happens at a much lower level of activity.

Exceeding SEL leads to a drop in thresholds for future exertion tolerance.
Resting (red bars) leads to an increase in thresholds for future exertion intolerance. This increase is slower than the drop from overexertion.
So here the person's rest periods are not enough to offset the overexertion and their limits drop over time.

The next 2 exertion bars (short, blue) show the person taking it easy in an attempt to recover. This succeeds partially.

The next 5 exertion bars (blue) show the person going back to their normal routine too soon. That means the person very quickly hits their already lowered SEL and soon after also the point at which full PEM is triggered (green line). The person is stubborn and fights through PEM, feeling ever worse. Any recovery achieved through resting is even slower than before.

The next 2 exertion bars (short, blue) are therefore very low, the person is in a crash and attempting to recover. This succeeds partially.

The next 5 exertion bars (blue) show the person going back to their normal routine much too soon. This time they hit not just SEL and PEM very quickly, they hit the critical point (yellow) that means full recovery to original SEL is no longer possible. That is shown by the last 6 exertion bars (short, blue) where the patient rests consistently and slowly improves. That improvement, however, levels off before reaching starting point levels.

 

[Ravn]

Will the current NIH intramural study - where patients spend 5 nights in a metabolic chamber - give us any idea about our basal metabolism? And about whether we're expending too much energy during "rest", especially in PEM?

 

[Peter T]

Sorry I am still struggling to get my head around the ideas, this week is not a good week, but this attempt to describe our activity limitations is important.

I do think it is useful to develop a description independent of any [hypothetical] underlying mechanism. The above graphs have used postulated calories burnt as the y axis (sorry can not be certain I have fully understood), though hopefully this modelling would still be valid even if this turns out not to be the key variable.

I have been exercised by the question what is the relationship between the very different activities/stimuli that can trigger PEM. Is their effect cumulative or not?

Say ‘x’ is the quantity that triggers PEM, and assuming there was a way to quantify very different activities/stimuli in the same units, then ... ....

For example for me physical activity, cognitive activity, noise, light and amount of time upright are all triggers of PEM. For me the PEM is the same regardless of what the trigger is. However they do not all behave in the same way, as noise might trigger distress and/or impaired cognition at a lower level than it triggers PEM, whereas physical exertion might not necessarily trigger brain fog or any distress before PEM kicks in. But putting this aside, are the different triggers cumulative or independent.

If they are cumulative then x/3 physical activity + x/3 cognitive activity+ x/3 being upright + x/3 noise should trigger PEM, as the total is one and one third x, which exceeds the trigger level. However if they are independent triggers then as no one aspect has reached x, PEM will not be triggered.

I suspect, though this is compounded by the fact that I now struggle to do more than one thing at a time perhaps because of brain fog, that sub PEM threshold they are not cumulative. That is as long as noise is not too loud, it does not impact on how far I can walk, as long as it is not too far, which does not reduce the amount of time I can remain upright as long as it is not too long.

In contrast for me once PEM has been triggered it lowers the trigger threshold for all other modalities, so x becomes smaller, for all. So if PEM is triggered by physical exertion, this reduces the amount of time I can remain upright and increases my intolerance of bright light.

So I am suggesting that though a number of systems are involved in ME (the systems involved may vary between individuals), in relation to PEM these systems operate independently up to a variable PEM trigger threshold, but that once PEM has been triggered in any one modality we then have multi system problems.

This also raises the issue of why more than one system is involved in ME? Personally I have found that over time more, and more varied, symptoms have become involved in my ME. Could it be that triggering PEM in one modality impacts the SEL (sustainable exertion limit) in other modalities, so that over time the SEL is lowered in other modalities such that day to day they also becomes an issue?

[edited - grammar corrected and some clarification of wording]