Chemobrain (& CFS): critical review & causal hypothesis [=somatoform via biomed]

[Bob]

It seems to me that they would like to 'prove' their hypothesis that "chemobrain" is a somatoform disorder triggered by biological changes. So they're targeting cancer survivors. It seems like dangerous nonsense to me. If they can do this with cancer survivors, then they can do it with any patient cohort. We need to get Walitt off the NIH study.

 

[Bob]

@Simon, thanks for highlighting this paper.

 

[Simon]

The bad news

The bad news is partly that the paper points in two contradictory directions, and emphasises psychosocial causes too. What makes this particularly troubling is an interview Brian Walitt gave about a presentation he made to the Annual Perspectives in Rheumatic Diseases conference in September 2015. It's about Fibromyalgia, not mecfs, but the current paper treats fibromyalgia and mecfs as having essentially the same cause.

VIDEO: Fibromyalgia doesn’t fit the disease model : Family Practice News

#MEAction helpfully provide a full transcript of this video, with slides, including such gems as

these atypical things are just a range of normal, that you’re not sick, bad, or weak, that you’re just dealing with the difficulties of just being a human.

NIH lead clinical investigator thinks CFS is psychosomatic | #MEAction

More anon, about how that meshes with many of the ideas expressed in this paper. I think that video probably deserves its own thread, if one hasn't been created already.

 

[Marco]

Note (mainly to self) that "physiologic" means "normal physiology" or normal physiological processes. So when the paper says: "Rather, accepting the possibility that chemobrain is related to that seen in somatoform illness provides a unique opportunity in examining the physiologic underpinnings of these illnesses", it is not suggesting that the illness has a physiological underpinning, but it is stating that there is no abnormal biology.

'Dysfunction' may be physiologic- do we object to terms like immune dysfunction?

 

[Large Donner]

So the onset of ME or fibro is caused by a chemotherapy type event mechanism in non cancer patients not being treated with chemo, who most often report a severe viral onset and have observable changes in cytokines, but its still psychosomatic?

They also have to claim, to back up this notion, that there are no side effects to chemotherapy.

 

[Marco]

If there are epigenetic changes, I struggle to understand how they can conclude that it's a somatoform disorder. It baffles me.


But isn't that a contradiction? If there are (epigenetic or cytokinetic) changes then isn't that a detectable physical abnormality?

What am I missing here? I don't understand how they are defining "somatoform". Have they redefined it to mean "subjective experience"? Or are they trying to assert that measurable physiological changes in the brain or "neurologic injury" must be observed for symptoms to be accepted as biological/organic in origin? I think perhaps it's the latter, or similar; They are neurologists and want to detect "neurologic injury" of some sort. If no neurologic injury is observable then it's a somatoform disorder. So perhaps they consider epigenetic or immunological changes to be irrelevant because they only consider brain injury to be relevant. Epigenetic or immunological changes can't directly cause neurological-type symptoms, in their view?

Maybe we should just ask him?

 

[Bob]

This is simply a new twist on an old idea: cytokines linked to chemotherapy trigger long-term changes in the brain that cause cognitive dysfunction.

I've found it very confusing, but I interpreted it differently from you: I thought that they're saying that there are no long-term physiological changes in the brain; That the brain is perfectly normal, apart from a change in thinking processes and neuroplasticity. So there are functional changes but no structural changes.

The fact that there are epigenetic changes seems to have no consequence in terms of defining it as a somatoform disorder, which I find baffling; They're saying that if there are no structural changes to the brain then it has to be a somatoform disorder, whatever other biological abnormalities are present. The possibility that the epigenetic changes could directly cause the symptoms hasn't been considered. They're assuming that fatigue etc, must originate from within the nervous system rather than from other biological processes such as the mitochondria.

That's my current interpretation, but it might change.

 

[Old Bones]

The bad news is partly that the paper points in two contradictory directions . . .

I agree. Not only did the "paper point in two contradictory directions", Walitt's interview seemed to as well. I watched the entire video, and found the content to be a confusing, jumbled mess. My opinion of what he was saying repeatedly switched from agreement (that he was "on our side"), to indignation (that his views were "way off base"), and back to at least partial agreement. In the end, I was left wondering if even he knew what he thought.

 

[Bob]

'Dysfunction' may be physiologic- do we object to terms like immune dysfunction?

Marco, "physiologic" specifically means "normal physiology". "Physiologic" does not have the same meaning as "physiological". You can say "physiological dysfunction" but you cannot say "physiologic dysfunction". Check out the meaning here: http://medical-dictionary.thefreedictionary.com/physiologic

I've only just discovered the meaning of this word myself. I had to look it up. The paper appears to have the opposite meaning than its intention if this word is misunderstood.

 

[Marco]

Marco, "physiologic" specifically means "normal physiology". "Physiologic" does not have the same meaning as "physiological". You can say "physiological dysfunction" but you cannot say "physiologic dysfunction". Check out the meaning here: http://medical-dictionary.thefreedictionary.com/physiologic

I've only just discovered the meaning of this word myself. I had to look it up. The paper appears to have the opposite meaning than its intention if this word is misunderstood.

I have a personal theory that the core pathology in ME/CFS is that the brain's microglia have been so sensitised that they respond abnormally to physiologic (as in normal) levels of physiological (too many physios) signals which is essentially what Younger found when he correlated leptin levels with fatigue. Is that physiological or physiologic? I would say physiological because the brain is behaving abnormally but can you point to a physiological reason?

That's the current challenge.

 

[Simon]

So many other things I'd rather do tonight than this (nothing would be good).

Anyway, just responding to a few points (not sure I'll even get to finish my 'bad news' points)

If there are epigenetic changes, I struggle to understand how they can conclude that it's a somatoform disorder. It baffles me.

I fear you are falling into that age-old dichotomy of trying to separate mind and body

Any long-term pysch state, inc depression and anxiety, is likely to have biological correlates, quite plausibly including epigenetic modification. Though there is no evidence presented of epigenetic changes in the brains of patients (for obvious reasons)/

The problem with things like fibromyalgia and other disorders that are of the neurologic systems of the brain is that the brain seems to have a duel existence. It exists both as a biological construct, but it also exists as sort of a psychological construct and we don’t really understand how the two go together yet

'Dysfunction' may be physiologic- do we object to terms like immune dysfunction?

That doesn't seem to be how the authors meant it, I'm afraid:

Cognitive dysfunction is the subjective experience when one has deficits in their cognitive function. Objectively measured cognitive deficits will be referred here as “cognitive impairment”

They state that ME/CFS is a somatoform disorder, and use a purported lack of abnormalities in cognitive tests as their evidence. But they cite only selective evidence in relation to cognitive testing. ME/CFS patients do demonstrate impaired cognition in tests, but only for specific types of cognitive processing. So the authors have outdated partial knowledge about the subject, leading to false conclusions.

As I said in my initial post, this point is broadly fair - the only consistent defect in mecfs is reaction time, and when do we ever say - 'damn, the main problem I get is slow reaction time'? Also my point re Susan Cockshell's work:

after a 3-hour session of cognitive testing of memory and attention, healthy controls took an average of 7 hours to recover, compared with 57 hours – more than two days – for CFS patients.

They may not be doing a good job of measuring real-world impairment with their tests

I've found it very confusing, but I interpreted it differently from you: I thought that they're saying that there are no long-term physiological changes in the brain; That the brain is perfectly normal, apart from a change in thinking processes and neuroplasticity. So there are functional changes but no structural changes.

Indeed, the do say that in some places but when the preamble is done oddly come down in favour of physiology. I found it a very confusing paper that faced two ways. I wonder if there were different viewpoints among the authors, that led to a rather self-contradictory text?

They're assuming that fatigue etc, must originate from within the nervous system rather than from other biological processes such as the mitochondria.

But like I said, plenty of researchers would agree with that, including Younger, Perry and Lloyd but probably a whole lot more too; it's certainly not a controversial view, though clearly not everyone would agree (but not everyone would agree on anything). It's my personal favourite, but there's no really robust evidence for it yet.

 

[Bob]

Thanks for your thoughts and notes, Simon.

They're assuming that fatigue etc, must originate from within the nervous system rather than from other biological processes such as the mitochondria.

But like I said, plenty of researchers would agree with that, including Younger, Perry and Lloyd but probably a whole lot more too; it's certainly not a controversial view, though clearly not everyone would agree (but not everyone would agree on anything).

I can understand why someone would think that the nervous system plays a central role in fatigue, but Wang et al. are also assuming (as far as I understand it) that there must be an observable abnormality in the nervous system i.e. a "neurologic injury" for there to be a biological illness. This goes much further than assuming that the nervous system pays a central role in fatigue. For some illnesses, the underlying cause of malaise and fatigue may be biological without any "neurologic injury" (as far as I'm aware) for example during a bout of flu; with flu, the virus is the underlying problem and the immune system signals to the nervous system that it should induce fatigue. The flu is functional/psychosomatic as far as Wang et al. are concerned, because there's no "neurologic injury", which seems like an extreme position. Or that's the way I understand the paper. But I may have it wrong.

 

[Bob]

Brain hurting. Need a rest!

 

[worldbackwards]

NIH lead clinical investigator thinks CFS is psychosomatic | #MEAction

Fibromyalgia appears to be a way that people experience suffering in their body, both from the way that their bodies are interpreted and the problems of the body, as well as the problems in their lives, as well as how societies tell us how to experience things. All those come together to create a unique experience in different points in time and right now that experience is–one of those experiences is fibromyalgia...

When you talk to patients with fibromyalgia and you ask them what they think about it, they can often provide you the answers about where they should go. People with highly spiritual feelings and believe in spiritual forces as potential ways to heal should be referred that way. People who believe in exercise should go that way. People who believe in Eastern philosophy should be referred that way.

The postmodernists are back, I see. Nice that the photo catches him in his best "I know nothing" pose as well.

 

[Old Bones]

Walitt said:
Fibromyalgia appears to be a way that people experience suffering in their body, both from the way that their bodies are interpreted and the problems of the body, as well as the problems in their lives, as well as how societies tell us how to experience things. All those come together to create a unique experience in different points in time and right now that experience is–one of those experiences is fibromyalgia...

When you talk to patients with fibromyalgia and you ask them what they think about it, they can often provide you the answers about where they should go. People with highly spiritual feelings and believe in spiritual forces as potential ways to heal should be referred that way. People who believe in exercise should go that way. People who believe in Eastern philosophy should be referred that way.

Blah, blah, blah!

 

[Forbin]

When you talk to patients with fibromyalgia and you ask them what they think about it, they can often provide you the answers about where they should go. People with highly spiritual feelings and believe in spiritual forces as potential ways to heal should be referred that way. People who believe in exercise should go that way. People who believe in Eastern philosophy should be referred that way.

Interesting. I can't really say where I should go, but I feel like I could tell him where he could go.

 

[sarah darwins]

Walitt seems to be having trouble with that tricky scientist / daytime TV presenter distinction. Lot of it about.

 

[adreno]

A lot of the problems with this paper (and others) is philosophical bankruptcy. The authors simply fail to define the theoretical framework needed for their argumentation, likely because they have very little understanding of the issues.

So, the epigenetic changes affects the mind, and then disappears, leaving only residual change in the mind? Or are the epigenetic changes still there in the brain? Do we have a mind at all, according to the authors, and is there interaction between mind and body? Is this a dualistic or monist argument they are presenting? A physiological process that creates a psychosomatic disorders, then disappears? Complete nonsense.

Until they get their theoretical framework, standpoint and definitions straight, this is all unintelligible nonsense.

 

[Simon]

I've finished rereading this study and found it very hard to comprehend, not least because the authors seem to be avoiding clearly stating their beliefs. Here's what I came up with

Commentary (summary first)

• The authors imply that chemobrain and mecfs/fibromyalgia patients make a lot of their symptoms, contrasting reported perceived cognitive dysfunction with little measured objective cognitive impairement,
  
• They propose the well-known hypothesis that temporary spike in cytokines related to chemotherapy treatment could lead to long-term changes in the brain responsible for chemobrain
• What's novel about their hypothesis is the assertion that all this is in the range of 'normal' ie this is a natural 'physiologic' process rather than abnormal patholgy (thanks, @Bob).
  
• They suggest that the psychological stress of chemo (and cancer) may play a role too
• They argue the long-term changes may be epigenetic (many long-term changes in the body are), but emphasise the mind and brain are intertwined ie explicitly avoid arguing for a biological driver

But the biggest concern I have is they take an unproven hypothesis about chemobrain, and effortlessly equate it with mecfs (and fibro) - then assert that studying chemobrain could reveal what causes mecfs. As opposed to, say, studying mecfs as it emerges.

They suggest the 'post-infectious' trigger of mecfs could be down to recall bias and seem unaware of the numerous prospective studies eg of glandular fever that track the development of mecfs, eg the Dubbo studies (below). Perhaps that's why they ignore the possibility that such postinfectious studies are both practical and a much more approrpiate, direct approach.
(Dubbo study: Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study | The BMJ)

Notes (work in progress)

Cognitive dysfunction is the subjective experience when one has deficits in their cognitive function. Objectively measured cognitive deficits will be referred here as “cognitive impairment”.

Do those symptoms reflect reality?

The authors express great scepticism over whether the problems reported by chemobrain patients are really that bad:

Despite the paucity of evidence for cognitive impairment, patients with chemobrain consistently report clinically important cognitive dysfunction that impair their daily function, in particular in regards to attention, concentration, for-getfulness, word-finding, multi-tasking, and organization. The clinical presentation of chemobrain is notable for the discordance between the subjective experience of cognitive dysfunction and objective neuropsychiatric measurements [29].

They go on to doubt that methodological issues are behind the failure to find cognitive problems, which implies the issue is one of perception by pateints who don't really suffer from what other people would regard as problems.

So let me fish out that Susan Cockshell study finding one more time, that hints at a more appropriate way to measure cognitive problems

after a 3-hour session of cognitive testing of memory and attention, healthy controls took an average of 7 hours to recover, compared with 57 hours – more than two days – for CFS patients.

Contrasting pathogenic "neuronal injury" with "somatoform" normal functioning

Currently, chemobrain is hypothesized to be the result of neuronal injury with consequent inadequate repair, abnormal brain remodeling, and corresponding neuroendocrine-immunological changes [34].
...[express scepticism of the evidence,which probably isn't too strong]
...The essential questions underlying the validity of the hypotheses underlying the current chemobrain concept, that of direct causality and neuronal injury, are not answered by the scientific literature to date.

A somatoform view of chemobrain would consider it as an atypical yet predictable subjective experience that result from the normal functioning of the brain rather than from an injury

Now with added epigenetics!
I'm not sure invoking epigenetics adds anything.

we hypothesize that the administration of chemotherapy agents initiates a cascade of biological changes, with short-lived alterations in the cytokine milieu inducing persistent epigenetic alterations. These epigenetic changes lead to changes in gene expression, alterations in metabolic activity and neuronal transmission that are responsible for generating the subjective experience of cognition

In a recent talk, George Davey Smith described epigenetics as 'the confused researchers friend': can't explain something? Just say it's epigenetics... It could be, but basically we still have a black box of a brain: changes in cytokines in the body somehow leads to changes in the brain, that leads to 'cognitive dysfunction'. But what's driving it?

Here is the now-familiar 'mind/body dualism is simplistic and wrong' cliam:

We emphasize that viewing chemobrain as a somatoform illness does not undermine its clinical legitimacy or trivialize the patient suffering that comes with it. All human experiences are psychosomatic ones whose existence is dependent on discoverable physiological mechanisms that are potentially susceptible to therapeutic manipulation.

More later.

Maybe. I find this all rather demoralising; it seems a step back rather than forward.

 

[Valentijn]

I know it's rather contradictory, but Walitt's underlying model of psychosomatic disorders (based on reading 10-12 of his papers), seems to be that basically:

1. The symptoms are imagined, or are an over-reaction to normal stimuli.
2. The onset of over-reacting can be triggered by something biological, including genes.
3. There is no damage or ongoing pathology.
   
4. Patients should not be treated for their reported symptoms.
   
5. Physiological differences are associated with the psychosomatism, but are also somehow normal and not indicative of a neurological or other biological disorder.

Basically, he seems to concede that there might be a partially physiological basis for the psychosomatic disorder, but there is no physiological basis for the symptoms being experienced. Genes cause people to think they have symptoms - the genes do not actually cause the symptoms. Chemo causes a cytokine spike which causes people to start thinking they have symptoms. Brain scans are the biomarker for psychosomatic disorders, and not important to actual physical functioning of the body.

In short, he's bat-shit crazy, just like all the other psychobabblers who go down this route when they can't deny the physical abnormalities in supposedly psychosomatic patients. He is taking a simple concept (biology causes symptoms) and inserting an intermediary factor in the form of psychosomatism (biology causes psychosomatism which causes perception of symptoms).

This is not logical or rational reasoning. It is persuasive writing, where someone starts with a desired outcome, and then generates data to support that outcome, or frames that data in the way which best suits them.

In this case, the desired outcome is that "Clearly these diseases are not biomedical." Why is that outcome desired? Insurance industry or public benefits ties? Investment in that theory, as part of their clinical practice, publishing history, and past abuse of patients based on that theory? The attraction of a theory which subjugates a large class of people who can't fight back? The need for easy answers in the face of overwhelming uncertainty?