Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease, 2024, Khalid A. Hanafy

We are only now starting to gain the tools that are sensitive enough to know what the pathology of less overtly severe clinical symptoms are. Newer generations of PET tracers, more advanced MRI methods like this one https://pubmed.ncbi.nlm.nih.gov/35622913/ are how we actually determine if the clinical symptom match the pathology in this case. Before the development of MRI, I presume it would have been incredibly easy to say a similar thing to a less severe MS patient. "You have some fatigue, gait issues, vison abnormalities and depression so nope, can't be anything wrong in the brain because if you really had demyelination you wouldn't be able to walk".

I'd argue that the researchers like Michael VanElazkker, Jarred Younger and Michelle James who are working on this in ME must have some idea of pathology and probably understand the clinical symptoms pretty well from interacting with patients. From what I can gather, it is the symptoms that led them to first hypothesize that some type of neuroinflammatory process is taking place given what they know about the pathology. I am surprised these researchers haven't put out more data, but from their recent talks many of their projects are expected to finish this year.

I certainly agree that I am not delirious. But the fact that a severely compromised BBB in catastrophic sepsis causes delirium does not necessarily tell us what happens if the BBB is less severely damaged. As with most things in the human body it is rarely all or nothing and almost always on a gradient. If you break your finger and can no longer bend it, that doesn't mean that hitting your finger on the table will have the same affect. The brain is so complex and has been so challenging to study because of its importance and difficulty in accessing it that there are many seeming possibilities that don't involve catastrophic damage. There are many well refenced papers that I have glanced over that seem compelling and if those who actually understand immunology cant be bothered to point out issues then that certainly seems like a problem.

 

But that argument is as long as a piece of string, so of little use. It seems to me very unlikely. The human body maintains itself free of degenerative changes over decades. If things 'flew under the radar' I think we would see progressive changes of one sort or another in all of us.

The main point is it actually makes no sense for circulating cytokines to engender local inflammation in brains. It is back to front of how they work - from outside to in, not inside to out.

It might well be. But these are completely different processes.

 

I am not convinced, to be honest. Yes it is easier to pick up things like demyelination early with MRI but that happened thirty years ago. Certainly in the field of ME I have not been impressed that any of the imaging picks up more than random noise.

Structural changes progress, so it is nearly always a matter of just being able to see things earlier. People who have had ME for twenty years still show nothing consistent on brain scans.

I think that we can be pretty sure that most people working in the field of ME and brain have no real understanding of pathology. I worked on rheumatoid disease, which has pathology you can carry around in a jar. Almost none of my research colleagues had any pathology training and could not have described the cells in the tissue. I did my doctor in a pathology department and for a year embarked on histology training before returning to clinical rheumatology because I thought working directly with patients was actually a better base for research.

As has been admitted at a major conference of neurologists, nobody actually knows what they mean by 'neuroinflammation'. It belongs to a new dictionary of buzzwords of a sort we did better without.

Well-referenced these days just means part of a current fad. I appreciate that things may seem compelling if you do not have a deep knowledge of all the relevant sub disciplines - histology and immunology in particular. But pretty much everything I have seen on ME brain appears to be written by people who do not understand the basic cellular dynamics. I am pointing that out here. Pointing out problems in science is traditionally done at peer review and that now hardly functions. Anything gets published.

And a lot of researchers working on ME or LC are not even clinicians so they don't really have any grasp the clinical problems. Sorting out disease mechanisms is a very difficult process that takes years of study before you are likely to be in a position to find a new lead. Most of what I see at the moment is re-hashing of old muddled ideas.You don't get anywhere until you realise that almost everyone is getting things confused and drawing false conclusions.

 

And apart from anything else there isn't any increase in circulating cytokines in ME, so the whole thing seems a dead duck.

 

Only to people obsessed with validation of their disorder. There have been hundreds, if not thousands, of papers on physiology, more than those on psychosomatic features, on it.

That some MECFS is caused by Long Covid is *NOT* an evidence that MECFS is post-infectious. It's only an evidence that Long COVID is post-infectious. If you disagree, feel free to show me ANY definition that says MECFS is post-infectious.

Long-COVID is actually unfortunate for MECFS in that it started the cycle all over again and repeating what's went on the past 40 years. People are again looking into viral cause that failed to prove for decades, look at muscle anomaly, which again failed for decades, or mitochondrial anomaly which focuses on fatigue only and doesn't explain none of neurological symptoms/PEM, etc, etc. They'll never find an answer there. It's colossal waste of time and money and hinderance against progress.

Against accomplished researchers like Iwasaki or Monje? Someone who thinks science deals with unmeasurable feeling? Do a quick pubmed search to come to a conclusion that OTS is a fraud? Let's not resort to authoritarianism: that is not scientific.[/QUOTE]

 

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Dr Byron Hyde

Non-Infectious M.E. Type Disease: I have not discussed noninfectious M.E.-type disease. Similar M.E phenomena can occur due to CNS injuries from toxic chemical injury. I have seen this in police officers who have fallen into toxic chemical ponds in pursuit of those suspected of criminal activity. I have seen it in farmers repeatedly exposed to pesticides and herbicides, in hospital and industrial workers and in military personnel in contact with toxic chemicals, specifically toxic gases. I will discuss these at a later date as Secondary M.E. They do have one thing in common, and that is they also have a diffuse CNS injury as noted on brain SPECT scans. The diagnosis is made by history, as the actual cases are very difficult to diagnose due to the inability to assess brain levels of toxins in a live patient. Often these Secondary M.E. diseases are more severe than the infectious M.E. cases.

I've known a few pwME who didn't experience a known viral onset. They all had a slow gradual onset.

 

GWI sleuth work has lead to a partiular chemical weapons disposal site, I've heard. IH/CCI cases also do exist and can't be ignored, though those cases seem to resolve once IH/CCI is corrected.

MECFS is rather well defined, by the symptoms. People who think it's post-viral, or certain MECFS is not real MECFS, are only extrapolating from their limited experience.

Those cases could be from chronic stress over the time. I know a few cases that is non-viral onset and are sudden. I'm one of them. So is Jamison Hill. I've also heard of cases of people with traumatic accidents developing MECFS.

 

Overtraining Syndrome - PMC (nih.gov) In particular, look at Table 2 from the ECSS definition. I can't find the original ECSS paper, but I'll post it when I do.

 

From table 2.

Symptoms of overtraining syndrome.

Fatigue, Insomnia, Anorexia
Depression, Irritability, Weight loss
Bradycardia, Agitation, Lack of mental concentration
Loss of motivation, Tachycardia, Heavy, sore, stiff muscles
Hypertension, Anxiety
Restlessness, Awakening unrefreshed

From the "Future Directions" section

"In a survey of the literature, psychomotor speed is known to be decreased in many different pathologies, most notably major depression and chronic fatigue syndrome, which share many characteristics with NFO/OTS"

So not identical then.

 

But you could make exactly the same argument about people think ME isn't post-viral!

Nobody knows. Nobody can know, because viruses don't play fair. They hit some individuals like a brickbat yet in others cause no symptoms, so people can develop post-viral illnesses without even knowing they had a virus.

 

Is "inflammation" required for glial cells to affect neural functions? Do the cells have to be in a visibly altered state? Cells are pretty complex, so it seems reasonable to me that an astrocyte (which is part of the BBB), for example, might respond in some way to a circulating cytokine. Maybe it only alters membrane transport of a chemical by a few percent (nothing to show up on MRI or serum assays), but is still enough to result in brainfog or other symptoms.

I will have to rethink my beliefs about ME. Back before I knew about ME, I had read about glia responding to IFN-g, and that seemed like a good explanation for my response 24 hrs after exertion. I hadn't bothered to check whether exogenous IFN-g crossed the BBB. It's going to be tough to shake 20-year old assumptions about cytokines crossing the BBB.

 

But does it actually make sense?
If there are circulating cytokines reaching brain that is an indication that something is wrong somewhere else. The hypothalamic cells responsible for controlling cortisol and temperature regulation are exquisitely sensitive to circulating mediators but I do not see any reason why a glial cell in any other part of brain should want to change behaviour just because there is a sign of something wrong somewhere else.

If cytokine levels are high enough there may be enough fever to produce delirium but that is not the situation in ME where the temperature is normal.

As far as I am aware the BBB is largely controlled by endothelial and vascular supportive cells. Astrocytes are deeper in brain parenchyma I think. I cannot see any advantage in the BBB changing if there are signals of inflmmation in other parts of th body.

I don't know if IFNg crosses BBB generally. It must access the cells in the thermoregulatory centre if it produces fever, but they are in a very special environment I think.

The other thing is that cytokines like IFNG mostly act at very short range at concentrations maybe 10,000 times higher than in circulation in micrometer or even nanometre spaces. The thermoregulatory cells do pick up the tiny levels but these are not the levels that activate macrophages in tissues. If you have an abscess on you right leg with cytokine overspill you do not get any obvious change in cell behaviour in the hands.

 

Nobody said ME isn't post-viral. Viral onset may be the most common onset, but it is not the only one. There are several onset triggers and too many people are looking at the viral onsets only with blinders on.

 

Nobody has problem saying their MECFS is post-viral. But there are some people who are quick to dismiss non-viral onset. There were people dismissing Jenn Brea's case, for example, despite her being diagnosed with MECFS with all requisite symptoms.

No, not exactly same. If they were, it would be called MECFS. OTS is pretty much like MECFS in that it is defined by symptoms, but there haven't been as much as effort to define/diagnose OTS since most OTS cases usually recover in days, weeks or months. It's like a PEM for athletes. OTS is diagnosed as MECFS however, if it lasts more than 6 months and "Long OTS" cannot be distinguished from MECFS. And yes, Long OTS do have PEM.

 

Well, ok, that was my words for "Long OTS" that lasts more than 6 months. Those are indeed diagnosed as MECFS because, well, they meet the MECFS definition after 6 months.

 

There is one crucial difference, in that 'OTS' involves a presumed causation, just as 'post-viral fatigue' or 'chronic Lyme' does. 'ME' is purely a syndrome diagnosis with no invocation of a cause. That has major implications for the way cases are selected and symptom associations are interpreted.

 

No, that's not what I'm saying. Saying MECFS is post-viral means viral infection is required for MECFS. I'm saying MECFS is just what MECFS definition defines, not post-viral or non-post-viral or whatever.

Really? I'd like a link of that. I'm not aware of any definition that requires post-infectious fatigue. If it indeed does, it is wrong.

You are not gonna get an argument from me on that.

Just look at the papers coming out on Long COVID. Many are pretty much regurgitation of those on MECFS, "Long COVID" on it instead of "MECFS". Some conflicts what's been found, like the musle study, and some are just a repeat, like entero/hpv/EBS/whatever virus reactivation.

My beef is that they would have made a whole lot more progress if they spent the billion they spent on Long COVID research to build on MECFS rather than starting from "clean slate" as they put it, exclusively for post-viral syndrome.

 

You are not gonna get an argument from me on that either. Overtraining syndrome, post-viral syndrome => MECFS. Same MECFS regardless of the trigger, as long as it lasts more than 6 months and meets the symptomatic requirement.