Make PEM central to ME research [blog post by me]

[neophyte32]

PEM was very difficult to understand at the beginning of my illness. I even felt that exercise was helping me—that it lifted the brain fog and the constant feeling of cold I was experiencing. It is so heterogenus.

Looking back four years later, however, I now realize that I was already experiencing PEM, but it would begin only a few minutes or an hour later: during a long conversation, after an MRI with a contrast injection, which made me worse every time, or after visiting a crowded museum… Not because of physical exertion.

Then I started taking tramadol, and its effects masked the symptoms for eight or nine months, apart from what felt like a permanent cold, pain in my right eye, and pressure inside my skull.

Then, in 2023, my PEM initially began to manifest as panic attacks and anxiety immediately after exertion, eventually escalating into episodes of tetany and convulsions…

How was I supposed to make sense of any of this? I was still only mildly affected, yet every major episode seemed to unlock a new burden—POTS being the first.

It is so heterogeneous… It is going to be extremely difficult to understand.

But how can we explain the constant cold symptoms, the chronic rhinitis, I experienced for a year and a half? Since becoming severe and bedbound, they have completely disappeared. So they really must have been linked to exertion.

I saw that Renegade Research had conducted analyses before and during PEM. I thought the work was very poorly done; there is a thread about it on Twitter/X. I won’t share it because, honestly, I found it really bad.

 

[duncan]

I'm actually talking about erroneous immune cell or cytokine signalling rather than latant virus or bacteria.

Understood. I don't think the Georgetown study I was in was looking specifically for pathogens either.

 

[Yann04]

Unfortunately the way most funding bodies and ethics review boards work, you already need to have data to show why you want to do a particular complicated/invasive/unconventional/resource intensive study. At least some concrete indication that any part of your theory is true. Other diseases can check that box from animal models, even if the model is less than ideal. We’re at a disadvantage on that front.

It’s a shame because surely the long term harm of not knowing what causes ME/CFS and the societal stigma coming from that is orders of magnitude more than the potential difficulties with biopsy studies that haven’t yet been done in ME/CFS and the like.

 

[Creekside]

I was still only mildly affected, yet every major episode seemed to unlock a new burden—POTS being the first.

Imagine that your ME mechanism initially only affects your <pick a random organ>. The change in that organ affects other organs and processes, which in turn could make them more susceptible to whatever ME produces. That in turn messes up some other organs/processes, which affects still more. In each individual, the initial change will be different, as will all the subsequent changes. Messy disease indeed.

 

[jnmaciuch]

It’s a shame because surely the long term harm of not knowing what causes ME/CFS and the societal stigma coming from that is orders of magnitude more than the potential difficulties with biopsy studies that haven’t yet been done in ME/CFS and the like.

Well yes that’s logical to you and me. Trouble is that it becomes quite difficult to actually paint the picture accurately for someone totally unfamiliar with the reality of ME/CFS.

They won’t be cognizant of the fact that asking a pwME to travel to a study location to give blood samples or doing a 10 min exercise test is actually exposing them to high risk of harm (even if you explicitly list it, it will just seem like a very distant risk to someone reading it). But when you say that home sample collection is necessary because this population is too ill to access otherwise, they see red flags about how you’re going to get this person access to medical care if you mess up the blood draw. And you’ll have you explain why you don’t have an experienced clinical specialist in ME/CFS at the helm. And this is all being presented to them in a templated written document, so you just have to hope youve adequately conveyed the desperation of the whole situation (and that they’ll believe you).

I’m somewhat exaggerating here to make a point—people do manage to get funding and ethics board sign off despite all the hurdles. I guess I’m just trying to give some context for why we tend to see so many of one kind of study and nobody is pursuing what seems obvious. It’s not that nobody thought of it or is willing to jump through some hurdles. It’s moreso that certain avenues are like trying to convince a bunch of people to give us the keys to their cars when we don’t even speak the same language.

 

[Creekside]

I think there's a bit too much emphasis on the "exertion" part. I expect it makes most people think of marathon running and what those professionals talk about as limiting factors (lactate buildup or whatever). That makes them dismiss PEM caused by raising your arm to brush your hair a few times, or other such activities that most wouldn't put in the category of "exertion". From the perspective of PEM, it doesn't require working muscles to the point of exhaustion. Bright light might trigger PEM for some people, but is hard to categorize as "exertion". I get a PEM-like response (can't distinguish it from when I did get PEM) from certain foods, which also doesn't qualify as "exertion".

To me, PEM is an increase in ME symptom severity following some sort of trigger, commonly an effect of physical or cognitive exertion. For some people, PEM involves new symptoms, but maybe those symptoms are simply below noticeable severity pre-PEM? My experience is that PEM was simply a rise in baseline symptoms, some of which fell below noticeable levels at times. Sometimes I had thigh aches constantly, other times it was gone but returned during PEM.

I don't recall seeing a clear definition of PEM, including its variants and versions (long-term crashes, immediate responses to exertion, etc) that are debatable as to being separate symptoms. Is the delay a bell curve centered on 24 hrs, with 1/10^6 having a delay of 1 minute, or is that latter response a different mechanism affecting symptom severity? Do all PEM symptoms show up at the same time, or do some have a further delay, which might indicate indirect effects? It's hard to argue the respective importance of studying something that we can't even define properly.

 

[duncan]

It's hard to argue the respective importance of studying something that we can't even define properly.

Yep. Ironically, it's challenging - and maybe a little backwards logically - to try to define something properly before it's studied.

 

[Creekside]

Though just speaking for myself, the lack of foghorn findings in all the other studies helps make it obvious that the constant mechanism must be something tricky to measure for some reason.

That's why I favor ME being neurological. It would only take a small change in some factors in a few brain cells to cause the observable ME symptoms, and our present technology can't measure such factors directly. What if it's the ratio of specific molecules inside short-range vesicles?

Subjects with reliable dramatic increases in severity during PEM might be helpful for observing what's changing. The finer the scanner can focus, the narrower the field of view, but which area of the brain to focus on? I can imagine a brain study AI, which takes all the brain scan data available, and hopefully makes useful discoveries of just what's going on when you sleep (or can't fall asleep), or feel pain, or think about a stressful relationship. Maybe it could identify why we feel lethargy and brainfog, and what factors change during PEM.

 

[Creekside]

Ironically, it's challenging - and maybe a little backwards logically - to try to define something properly before it's studied.

It's an iterative process: start with a broad definition, see where it works and where it fails, and adjust.

For cohort selection, does the subject have to have a PEM delay of 24 hrs +/- 4 hrs or +/- 20 minutes? Maybe it does make a difference. Is the definition of PEM limited to a small subset of symptoms, or does it cover 10,000 different symptoms? You have to start with some limitations to the definition.

 

[ScoutB]

If we wouldn't get worse from it, why shouldn't we try and get our own lunch or sit up on a chair in the waiting room or talk to a doctor for an hour straight?

I think this is where the inhumane treatment of pwME/CFS casts a long shadow. Imo there is nothing we could learn about PEM (its cause, effects etc.) that would mean pwME/CFS should be doing more. My own experience has also been that exertion seems to can cause long term worsening. As you say, we've all tried and been forced to stop, and on some level are constantly trying, in the sense that whenever symptoms abate we start naturally doing more. But it shouldn't really be necessary to make this argument. In other contexts, various forms of self-limiting illness, illness with visible or well understood causes, society is perfectly happy to accept that some nebulous combination of baseline 'unpleasant' sensations plus acute worsening of symptoms on increased activity disables the sick person. Our bar for accommodations and support should be lower than 'this person is at risk of losing the power of speech'...