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

[Eddie]

Everything has to be kept in perspective - at least to an order of magnitude. This is what these people trying to spin these stories have lost sight of. Fifty years ago we tried to relate things to what we could see clinically and on pathology - in proportion. Nowadays people with no idea of pathology and often not much of clinical practice dream up stories that make no sense.

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.

Part of the problem I think is that the gross pathology we used to see in the 1970s has largely gone. It may to some extent have been replaced by the pathology seen in intensive care medicine with complications of things like heart transplantation. But I can see no useful link between the activation of hypothalamic cells in flu and neuroinflammation. In someone dying of catastrophic sepsis the blood brain barrier will be at risk. In ME I see no possibility of any cytokine storm that could have any significant effect on BBB. The PWME writing posts here are not having delirium or half unconscious with cytokines. They seem to me to be totally on the ball.

And I think that applies to those who are very ill with ME too. Alem Matthees managed to turn the UK FOI system on the BPS people despite being seriously unwell. If your BBB is dodgy that simply isn't possible. You are lucky to know what day it is.

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.

 

[Jonathan Edwards]

But could it be a matter of degree? A chronic low-grade situation that flys under the radar, lacking the associated features that are overt in the acute/ICU context?

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 may not be cytokines crossing into brain parenchyma drawing in immune cells, it may be other things affecting BBB integrity, allowing transgression of unexpected substances such as fibrinogen. It may be immune cells accumulating and activating at the CNS borders, eg Brain borders at the central stage of neuroimmunology (2022, Nature)

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

 

[Jonathan Edwards]

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.

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.

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.

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.

 

[Jonathan Edwards]

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

 

[poetinsf]

1. The dominant paradigm has, until recently, been the psychosomatic one.

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.

3. The emergence of Long-Covid seems to me a pretty good piece of evidence that this is post-infectious. Not definitive, but of considerable weight.

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.

He does have a 50 year research and clinical career, with some real successes, behind his opinion.

You have...?

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]

 

[Mij]

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.

You might interested in this thread

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.

 

[poetinsf]

You might interested in this thread

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.

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.

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

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.

 

[poetinsf]

Please could provide reference or references that show this?

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.

 

[Trish]

1. The dominant paradigm has, until recently, been the psychosomatic one.

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.

I don't understand what you are saying here. Sean's statement that the psychosomatic paradigm has been the dominant one until recently is factually accurate in both clinical appoaches to treatment and in research funding in many countries until very recently. Certainly so in the UK, Australia, most of Europe, less so in the USA I think. Numbers of papers are not what influences clinical practice or funding bodies.
What do you mean by 'people obsessed with validation of their disorder?

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.

I'm having trouble following your line of reasoning, @poetinsf.
Am I right in saying you are arguing that because not everyone who fits current ME/CFS diagnostic criteria is aware of a preceding infection that triggered it, therefore ME/CFS is not post-infectious?

Even the now discredited Oxford criteria which only required chronic disabling fatigue, not PEM and other symptoms, specifically included post-infectious fatigue along with some psychiatric conditions such as depression.

Other diagnostic criteria focus on symptom lists, not on predisposing factors or causes. That's not exclusion of post-infection, and researchers and clinicians of both the biomedical and psychosomatic persuasion acknowledge that the most common trigger of ME/CFS by whatever definion is an infection.

Other recognised triggers include physical trauma such as surgery or accidents and vaccination.

The key point is that if someone fits current diagnostic criteria, then they have ME/CFS, including those with Long Covid who fit the ME/CFS criteria. It's up to them and their physicians whether they add ME/CFS to their medical notes, or not.

That all says nothing about what the ongoing biomedical processes are causing the symptoms of ME/CFS. Nobody yet knows whether it's viral persistence, or something triggered by the virus or other trigger that upsets homeostasis and appears to be hard to reverse.

On overtraining syndrome, this 2022 review paper suggests it hasn't even been properly defined, let alone researched.
Overtraining Syndrome Symptoms and Diagnosis in Athletes: Where Is the Research? A Systematic Review
The symptom lists I found didn't include PEM, and none of them indicated that OTS is a long term debilitating condition, rather that it's a temporary setback reversed by rest, and gradual build up back to a more sensible training regime.

Whether athletic overtraining can trigger ME/CFS I don't know.

I don't understand why you suggest Long Covid is a disaster for ME/CFS research. The 40 years of existing ME/CFS research is lots of papers, but compared with other equally disabling diseases, miniscule, with only a handful of tiny studies looking at each aspect such as mitochondria and few if any replicated.

Given that you seem to want to dismiss a lot of research areas, perhaps you could explain what you think the cause and biology of ME/CFS is.

 

[Andy]

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.

 

[Trish]

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.

I agree post-viral is not the only trigger of ME/CFS, as explained above. It's fine for any individual to say their ME/CFS is post-viral.

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.

The list of symptoms in table 2 has some overlaps with ME/CFS, but is not the same as any definition I know of ME/CFS. It includes more psychological symptoms such as depression, anxiety etc, and doen't mention PEM.
Diagnosis is made after a couple of weeks, not 6 months as for ME/CFS and the article specifies that mood disturbance is required for diagnosis.
This sounds much more like burnout than ME/CFS.

 

[Kitty]

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

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.

 

[Creekside]

The main point is it actually makes no sense for circulating cytokines to engender local inflammation in brains.

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.

 

[Jonathan Edwards]

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.

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.

 

[poetinsf]

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

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.

 

[poetinsf]

I agree post-viral is not the only trigger of ME/CFS, as explained above. It's fine for any individual to say their ME/CFS is post-viral.

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.

The list of symptoms in table 2 has some overlaps with ME/CFS, but is not the same as any definition I know of ME/CFS. It includes more psychological symptoms such as depression, anxiety etc, and doen't mention PEM.
Diagnosis is made after a couple of weeks, not 6 months as for ME/CFS and the article specifies that mood disturbance is required for diagnosis.
This sounds much more like burnout than ME/CFS.

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.

 

[poetinsf]

"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.

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.

 

[Jonathan Edwards]

OTS is pretty much like MECFS in that it is defined by symptoms,

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.

 

[poetinsf]

Am I right in saying you are arguing that because not everyone who fits current ME/CFS diagnostic criteria is aware of a preceding infection that triggered it, therefore ME/CFS is not post-infectious?

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.

Even the now discredited Oxford criteria which only required chronic disabling fatigue, not PEM and other symptoms, specifically included post-infectious fatigue along with some psychiatric conditions such as depression.

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.

The key point is that if someone fits current diagnostic criteria, then they have ME/CFS, including those with Long Covid who fit the ME/CFS criteria. It's up to them and their physicians whether they add ME/CFS to their medical notes, or not.

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

I don't understand why you suggest Long Covid is a disaster for ME/CFS research. The 40 years of existing ME/CFS research is lots of papers, but compared with other equally disabling diseases, miniscule, with only a handful of tiny studies looking at each aspect such as mitochondria and few if any replicated.

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.

 

[poetinsf]

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.

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.