Measures of outcome for trials and other studies

[eafw]

To me, the question is, "would the activity monitor detect the postexertional malaise period?

My guess is that it usually would, but is that sufficient for a clinical trial???

If activity drops sufficiently during PEM then you'd see it on a step counter but it would be good to have some other measure. Does anybody know what actually is going on during the PEM phase, pretty sure this has never been investigated (apart from the 2nd day CPET) ?

For something rough and ready we are back to heart rate, reaction times, memory tests, and self reports. There is a blood lactate self test that athletes use but not sure how relevant that would be. Actimeter moniter on its own would not be enough anyway.

 

[MeSci]

Other things to measure that may reflect health and activity levels: muscle bulk.

This is being discussed a little in another thread at the moment but am reminded that I "accidentally" had mine measured when having an ultrasound scan on a dodgy knee. Asked the technician if the band of fibres we could see was my muscle and it wasnt, the 3cm (on screen) band was my tendon with about 1mm of muscle barely visible above it.

Looked it up and apparently it's a reliable (and cheap and easy) way to measure it

http://www.ncbi.nlm.nih.gov/pubmed/11834114

That may be one of the 'individual'/'optional' measures, perhaps? My musculature feels pretty good again after I got rid of the layer of fat that had seemed to be enveloping the muscles for years. (I achieved this through diet and supplements, BTW, not exercise).

 

[MeSci]

If activity drops sufficiently during PEM then you'd see it on a step counter but it would be good to have some other measure. Does anybody know what actually is going on during the PEM phase, pretty sure this has never been investigated (apart from the 2nd day CPET) ?

For something rough and ready we are back to heart rate, reaction times, memory tests, and self reports. There is a blood lactate self test that athletes use but not sure how relevant that would be. Actimeter moniter on its own would not be enough anyway.

This Phoenix Rising article suggests perhaps that lactate may be useful, but maybe we don't know enough yet about expected levels to use it as a measure?

And this one may suggest other possible exertion-related measures.

EDIT: Here is the forum version of the second article. (I find it easier to read those.)

 

[Marco]

so the exertion can be cognitive or physical (or an orthostatic stressor). Exertion does not necessarily mean activity. Exertion could be muscular exertion without any walking. The exertion could be from the orthostatic stress of standing for too long of a period or an cognitive task. An activity monitor would not pick up these exertions that causes PEM.

To me, the question is, "would the activity monitor detect the postexertional malaise period?

The reality is complicated but I feel we're going to have to go for good enough rather than perfect. What I outlined was just a first cut suggestion but there is some cross referencing if we were monitoring activity continuously (fitbit etc) and self reporting core symptoms daily.which include PEM, and either cognitive impairment or orthostatic intolerance.

If PEM follows a cognitive task or orthostatic intolerance you would likely score appropriately as you would PEM. The reduction on activity measured by the fitbit could be correlated with these subjective symptom scores.

 

[Jonathan Edwards]

An ME/CFS battery?

What we could end up with is a battery of subjective and onjective tests measuring function/activity and symptoms periodically and continuously. Something like :

• SF36-PF at start, middle and end points (subjective)
• 
  
• Cognitive measures at start, middle and end points (objective)
• 
  
• Autonomic function start, middle and end points (objective)
• 
  
• Continuous (daily?) monitoring of a short list of key symptoms including one individual choice (subjective)
• 
  
• Continuous, or perhaps over discrete 1 week periods, activity monitoring (objective).

Of course some thought would have to be given to how these are scaled and score to produce thresholds amenable to construct a single composite outcome measure.

That looks very plausible. Although it is nice to try to make clean logical divisions between elements, the reality for the ACR grading is probably that it seemed a sensible and robust mix. Your suggestion may have the same pragmatic edge.

 

[Jonathan Edwards]

We could do with a summary of the state of play in the thread so far, I know I've pretty much lost the plot now in terms of what's what and what's needed.

Prof Edwards, as the OP - what's your take, have your initial questions been properly addressed and any follow up questions or clarifications wanted ?

I think a lot of useful ground has been covered and Marco's proposal looks to me like a very good stab at putting it all together.

 

[Marco]

I think a lot of useful ground has been covered and Marco's proposal looks to me like a very good stab at putting it all together.

Thanks Jonathan - sounds like I've redeemed myself a little

 

[A.B.]

Is this discussion for the UK Rituximab trial or something else?

 

[Jonathan Edwards]

Is this discussion for the UK Rituximab trial or something else?

It is not in relation to any particular trial. It came up in my mind in relation to discussions about trials that have occurred in the past but seemed relevant to all trials that might be done in the future.

 

[Bob]

I think Jonathan has read this, but I thought others might be interested, seeing as it's pertinent to this thread:

Assessing Outcomes
Jennie Spotila
March 31, 2015
http://www.occupycfs.com/2015/03/31/assessing-outcomes/

 

[Jonathan Edwards]

Yes, I saw this on another thread. It is interesting and encouraging to see the FDA is at least taking an interest. I would be interested to know about specifics.

The worry about 'clinical outcome assessment' as a term is that it has been associated with audit. Audit is the business of departments or specialities assessing how well their patients are doing in order to judge the quality of the care provided. An assessment is made and then an adjustment to service policy is made and then another assessment is made to see if patients are doing better.

The problem with audit is that it does not involve any of the formalities like treatment blinding that you factor into trials. So it is sort of 'research-lite' and research-lite pretty much equals bad research, as we all know. Audit has become a compulsory part of service provision in the UK but that is pretty ironic if it is open to all the problems of bad trials.

On the other hand the FDA is principally concerned with formal testing and licensing as I understand it and it may well be that they are considering COA in terms of what would be used in formal trials. I hope they have a group of people who can create something robust. In the rheumatology field the FDA has had some good rules about measures but has also been absurdly narrow minded about how some of them are used, making drug companies do trials that do not generate the best sort of information. They have had categories that drugs have to be registered under even if the drug might work in such a different way that the category is inappropriate. But in time things tend to come out in the wash and this looks like a positive development.

 

[Eeyore]

I don't think we should measure fatigue. I don't think it's really a key part of the illness. The original definitions of ME do not describe fatigue as being a defining symptom. This is the problem with the CFS name vs ME or SEID. I was reasonably happy with the IOM's recent work.

For me, I feel mostly ok if I don't do anything, but even minor physical exertion can have dramatic effects. The fatigue for me in that scenario is closer to how one would feel with the flu - it's sort of like an "illness behavior" type of symptom. You feel malaise, low motivation, and don't want to get up and do anything or move around.

I do sleep poorly - I wake up a lot in the middle of the night, and the quality of sleep is rather poor. I don't often nap during the day anymore. The problem is that going to get the mail at the end of the driveway can be exhausting when I'm in bad shape.

I also did very poorly on a CPET - not the 2 day, just the 1st day, i was at 56% of predicted VO2 max. The pulmonologist thought I had DCM, and sent me to a cardiologist for a stress echo - totally normal. Heart rate went up to almost 190, bp rose to over 200 systolic. No abnormal wall motion, no ekg abnormalities, and the echo looked normal. The only thing noted was a hyperdynamic left ventricle - about 88% ejection fraction - and some mild left ventricular hypertrophy (and thickening of the IVS). It was borderline though. I did not desaturate.

After I exercise like that, I get EXTREMELY shaky. I can't hold a glass w/o spilling for a few hours. I have trouble standing up. I had to stop the test finally because I was beginning to have trouble seeing/focusing and I was becoming lightheaded.

The "fatigue" in CFS is mostly a post-exertional intolerance, hence SEID. For me, it definitely does not feel like I need to sleep - more like I need to lie down and rest. It can take way too long for the body to reestablish homeostasis.

 

[Valentijn]

I don't think we should measure fatigue. I don't think it's really a key part of the illness. The original definitions of ME do not describe fatigue as being a defining symptom. This is the problem with the CFS name vs ME or SEID. I was reasonably happy with the IOM's recent work.

That's my thought as well. I wouldn't even describe fatigue as being a major issue, though I do see the use of it in the diagnostic process. In the beginning, the patient doesn't know WTF is going on and hasn't connected their symptoms to OI or exertion. At that point "fatigue" makes for a decent, if vague, starting point.

 

[lansbergen]

I don't think we should measure fatigue. I don't think it's really a key part of the illness. The original definitions of ME do not describe fatigue as being a defining symptom.

For me, I feel mostly ok if I don't do anything, but even minor physical exertion can have dramatic effects. The fatigue for me in that scenario is closer to how one would feel with the flu

In the early years when I still could do a lot, I could drive long distance, do what I had to do and drive safely back but when I got home and turned the engine of an overwelming fatique hit .

 

[MeSci]

I don't think we should measure fatigue. I don't think it's really a key part of the illness. The original definitions of ME do not describe fatigue as being a defining symptom. This is the problem with the CFS name vs ME or SEID. I was reasonably happy with the IOM's recent work.

For me, I feel mostly ok if I don't do anything, but even minor physical exertion can have dramatic effects. The fatigue for me in that scenario is closer to how one would feel with the flu - it's sort of like an "illness behavior" type of symptom. You feel malaise, low motivation, and don't want to get up and do anything or move around.

I do sleep poorly - I wake up a lot in the middle of the night, and the quality of sleep is rather poor. I don't often nap during the day anymore. The problem is that going to get the mail at the end of the driveway can be exhausting when I'm in bad shape.

I also did very poorly on a CPET - not the 2 day, just the 1st day, i was at 56% of predicted VO2 max. The pulmonologist thought I had DCM, and sent me to a cardiologist for a stress echo - totally normal. Heart rate went up to almost 190, bp rose to over 200 systolic. No abnormal wall motion, no ekg abnormalities, and the echo looked normal. The only thing noted was a hyperdynamic left ventricle - about 88% ejection fraction - and some mild left ventricular hypertrophy (and thickening of the IVS). It was borderline though. I did not desaturate.

After I exercise like that, I get EXTREMELY shaky. I can't hold a glass w/o spilling for a few hours. I have trouble standing up. I had to stop the test finally because I was beginning to have trouble seeing/focusing and I was becoming lightheaded.

The "fatigue" in CFS is mostly a post-exertional intolerance, hence SEID. For me, it definitely does not feel like I need to sleep - more like I need to lie down and rest. It can take way too long for the body to reestablish homeostasis.

I don't get low motivation with PEM. I still want to do things and am frustrated at my difficulty in doing things.

Interesting that you have visual problems after extreme exertion. So do I. Sometimes with PEM I get a change in focal length, so that I have to switch to wearing different glasses for a few days.

 

[Eeyore]

@Valentijn - Yes, I think a lot of patients describe these odd symptoms as "fatigue" because they really are very difficult to describe. I don't believe anyone w/o ME can understand what ME feels like. Even very supportive family members don't always get it. It's no their fault - I just can't really describe it.

I went from hiking in the mountains of New Hampshire in the best health of my life to unable to walk up a flight of stairs without all my muscles shaking uncontrollably. I had to give up playing the piano because my hands - perfectly still at rest - would shake so much from playing the piano that I couldn't hit the right keys! I had one doctor once who studied exercise physiology who said that was a problem with oxygen delivery or use or energy production, especially in the pattern I'd get. That seems more accurate to me.

I think it's different for all patients to a degree. Except at my worst moments, my body seems able to delivery O2 and make enough energy to make me comfortable if I'm recumbent (lying or sitting, both work ok, if legs are up). I miss the active lifestyle I used to enjoy. Forget the hiking, I miss just being able to go visit with friends for a day and keep up doing normal things.

I think many of the intolerances people report are just that we don't have reserve to compensate. i.e. Everyone probably gets worse with alcohol, but if you start from a good place, you can manage, whereas if you're scraping by as it is, you're in trouble.

 

[duncan]

I'm a bit unclear as to how O2 delivery would correlate with intellectual exercises, or increased emotions, or simply the act of focusing or concentrating. All of these elicit a severe response in me, and it is usually a systemic one. I believe this is PEM, but cannot say for certain.

Also, the extra burden on my brain delivers a faster negative consequence, or penalty, than does a conventional "physical" exercise like lifting or walking too far. In the latter, the penalty may take 48 hours or more to register. With focus or concentration, it can come within a day, sometimes less than half a day.

I suppose there is an argument that says increased burden on the brain raises O2 demands.

 

[Eeyore]

@duncan

Interesting, and different from my experiences. I have not experienced prolonged intellectual effort leading to any form of relapse. I do have my periods of brain fog, but they usually are either random or subsequent to physical activity. Mental activity does not seem to be a stressor for me.

Strong (especially negative) emotion can be a stressor - likely due to catecholamine release and sympathetic activation (which, interestingly, occurs with physical exercise too).

Studies I've read suggest that while the brain uses a great deal of energy (about 20% of the total energy used in the human body), whether you are thinking hard or vegging out doesn't affect the energy demands.

I think the best insights into brain fog were made by Dr. Jay Goldstein. It's likely a problem with filtering what is and is not important, which functionally creates a deficit in working memory as our brains are trying to balance too many stimuli at once. He gives much more detailed and scientific explanations, but that is the gist of it as I remember it.

 

[duncan]

We are all a little different in our own manifestations, yes?

I have taken many neuro-cognitive tests over the years. I invariably do better on tests where I travel a short distance and then take the 6 hour tests. When I have to travel far - say to the NIH, and I have other tests before the neuro-cognitive - I perform poorer. Poorer on judgement scales, on IQ, on memory - poorer across the boards.

So what I do, and the order in which I do it, can have a profound effect on my intellect. Same is true for concentrating. I can be a passenger in a car, and I may suffer from vertigo as my vestibular system has been damaged. But if I am doing the driving, I will suffer a vertigo attack, sure as can be - there is no maybe about it.

But I am also positive for neuro-borreliosis, so that too may be what is at the root of my cognitive issues, and what I think are manifestations of PEM, are not.

It gets peculiar when you have valid diagnoses for both, and I know many on this Forum who are ICC positive for ME/CFS and 2-Tier CDC compliant for Lyme. I know the symptom/cause permutations make me want to just sway whichever way the wind blows on any given day, in terms of which disease is pulling my strings..

 

[Eeyore]

True - I have never tested positive for Lyme nor do I have any reason to suspect it, so it's a bit simpler for me!