A – A PERSONAL PERSPECTIVE ON ‘ME/CFS’
I want to make a controversial and potentially unpopular proposal: that ME/CFS is not a discrete disease in any objective sense and that attempting to more rigorously define a ‘pure’ ME/CFS cohort is futile.
In Parts I to III, I set out what I suggest is a plausible case for the core pathology underlying ME/CFS being a neuroinflammatory vicious cycle involving a glutamate/GABA imbalance, oxidative stress and mitochondrial dysfunction and suggest that this neuroinflammatory state also underlies other (previously unassociated) conditions. Before attempting to demonstrate how this model can explain the symptoms of ‘ME/CFS’, I want to make a controversial and potentially unpopular proposal : that ME/CFS is not a discrete disease in any objective sense and that attempting to more rigorously define a ‘pure’ ME/CFS cohort is futile.
A heterogeneous disorder or a man-made construct?
Any hypothesis, however tentative, needs to appear to be consistent with what is already known about the condition and herein lies the first problem; ‘What is already known’ about ME/CFS varies depending on how a researcher interprets the disorder.
The possibility that ME/CFS is a heterogeneous disorder is often raised as a potential confounding factor in research resulting in inconsistent or contradictory findings or in a failure to replicate findings.
It should now be clear from Parts I to III that I propose a common neuroinflammatory process underlies a range of ‘psychiatric’, neurological and neurodegenerative conditions including the ‘state’ labelled ME/CFS. How this neuroinflammatory process affects an individual (and hence the range of symptoms expressed and diagnostic label applied) may depend on a range of factors including genetic predispositions, developmental stage, gender and environmental ‘insults’.
From this perspective ‘ME/CFS’ does not exist as a distinct disease entity with potentially specific biomarkers
From this perspective ‘ME/CFS’ does not exist as a distinct disease entity with potentially specific biomarkers. What does exist is a pattern of symptoms that is broadly similar and sufficiently distinct from other conditions to lead to a ‘diagnosis’ of ME/CFS and not autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), Alzheimer’s or any of the other neuroinflammatory ‘labels’ discussed previously. Indeed this is the very essence of a ‘syndrome’. For the purposes of this discussion, however, the term ME/CFS will be used to refer to this group (rather than the unwieldy ‘patients whose broadly similar pattern of symptoms has resulted in them being given a label of ME/CFS’).
Even within those symptom patterns that can be matched to a specific diagnostic label, such as ADHD, there are recognised sub-groups including hyperactive, inattentive and mixed types.
I suggest that an abnormal balance between glutamate and GABA underlies all these conditions
I suggest that an abnormal balance between glutamate and GABA underlies all these conditions and that high or low glutamergic states can be found, at times, even in the same disorder. While that may appear counter-intuitive, it appears that the impact of glutamate on signal transmission/information processing follows a U-curve and that both high or low levels are deleterious. Glutamate levels may also be high in one brain region and low in another complicating the task of identifying glutamate dysregulation as an etiological factor but also helping to explain how the same process can result in such a wide range of symptom complexes.
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The hyperactive type of ADHD, for instance, appears to be associated with a hyperglutamatergic state (a high glutamate to GABA ratio – Courvoisie et al, 2004) while the inattentive type may be associated (like schizophrenia – Seeman, 2009) with a hypoglutamatergic state.
‘Atypical presentations and co-morbidity’
The situation is further complicated (if you conform to the convention that each labelled condition is a specific and discrete disease state) by ‘atypical’ presentations and ‘co-morbid’ conditions. Indeed, the high levels of atypical presentations found in these disorders suggests a fluidity is present that transcends traditional disease boundaries. In the proposed schema there is no ‘atypical’ or ‘co-morbidity’, only individuals where the symptom complex (including symptoms that do or do not fit within neat diagnostic boundaries) directly results from a neuroinflammatory state. This is a far more parsimonious explanation than to suggest that each ‘co-morbid’ condition arose simultaneously but from different underlying pathophysiologies.
Do ‘strict’ definitions such as the Canadian Consensus or International Consensus Criteria Help or Hinder?
This logically leads to a likely to be contentious proposal that the exclusion of patients with ‘co-morbid’ conditions such as major depressive disorder (MDD), ADHD, fibromyalgia, anxiety, obsessive compulsive disorder (OCD) or recognized neurological conditions, in the hope of obtaining a ‘pure ME/CFS’ cohort, may actually result in skewing research findings in the direction of what best conforms to the case definition of ME/CFS as a discrete entity rather than illuminating the underlying pathology affecting unique individuals.
This may be a contentious proposal but it’s consistent with recent findings that alterations of a single gene may increase the risk of developing a wide range of ‘psychiatric’ conditions. A recent Lancet publication (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013) reports the results of a very large genome wide study to :
“identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia”.
You may recall that all of these disorders have been previously discussed as being associated with a sensory gating deficit, potentially a sign of an underlying neuroinflammatory state. The consortium found specific single nucleotide polymorphisms (SNPs) common to all these conditions particularly calcium-channel activity genes and concluded that :
‘”These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology” (the classification of diseases) “informed by disease cause.”
Commenting on the findings in the New York Times (NYT, February 2013) reporter Gina Kolata states :
“The findings strengthen an emerging view of mental illness that aims to make diagnoses based on the genetic aberrations underlying diseases instead of on the disease symptoms.”
and that the paper reports :
“distinguishing psychiatric diseases by their symptoms has long been difficult. Autism, for example, was once called childhood schizophrenia. It was not until the 1970s that autism was distinguished as a separate disorder.”
Symptom-based diagnoses have concluded these are separate psychiatric disorders but this analysis suggests they share core physiological similarities. Similarly ‘ME/CFS’ may be just one manifestation of an underlying neuroinflammatory state whose presence has been obscured by symptom-based diagnostic labels. Instead of a more concentrated focus on subgroups in ME/CFS (aka using the CCC), the success of the Cross-Disorder Group suggests casting a broader net could illuminate core physiological abnormalities not just in ME/CFS but across a range of disorders.
The Cross-Disorder study suggests a) that core abnormalities can manifest themselves in startlingly different ways; attention-deficit disorder doesn’t look anything like schizophrenia, which suggests we might very well be in for some surprises with ME/CFS when all is said and done.
Given the considerable overlap in symptomology and ‘co-morbidity’ with other conditions with the possibility that the same neuroinflammatory state may underlie them all, does it really make sense to try to restrict research to conform with increasingly more rigorous case definitions?
The previous papers have been written from the perspective of my experience of my ‘ME/CFS’ (‘Wired and Tired’) which would appear consistent with a hyperglutamatergic state. It is possible that, like ADHD, within the label of ‘ME/CFS’ there are subgroups (perhaps including those whose symptoms tend towards lethargy and constant fatigue) where a hypoglutamatergic state predominates.
Given the considerable overlap in symptomology and ‘co-morbidity’ ME/CFS shares with other conditions does it really make sense to try to restrict research to conform with increasingly more rigorous case definitions? The NIH’s recognition that physiology often ignores disease boundaries resulted in the NIH Roadmap and the ‘Common Fund’ The ‘Common Fund’ funds research that jumps not just disease boundaries but Institute boundaries.
Program areas must cut across missions of multiple NIH Institutes and Centers, be relevant to multiple diseases or conditions, and be sufficiently complex to require a coordinated, trans-NIH approach. NIH Common Fund
It may be that that ‘lumping’ ME/CFS in with other conditions is more likely to identify the shared underlying pathology while ‘splitting’ into sub-groups may help identify specific etiological factors that triggered the neuroinflammatory state.
Of course if the range of symptoms displayed depends on individual genetic predispositions, gender, life experiences including pathogens encountered etc. then ‘splitting’ could carry on indefinitely down to individual level. In the study of psychological ‘individual differences’ this has been referred to as describing a personality type as a “left-handed, ﬁfty-three-year old introverted Isle of Wight rat-catcher”.
All of the above would suggest that attempting to explain each individual’s symptoms is somewhat futile. Nevertheless, since ME/CFS patients have been grouped together under a single label and since case definitions purport to accurately describe that label then the proposed hypothesis should at least be consistent with that description and any associated consistent research findings. Next up, then I look at whether a single neuroinflammatory condition could explain the core symptoms of ME/CFS.
The Neuroinflammatory Series by Marco
- Not Fatigue After All? New Model Suggests Other Symptoms Better Explain Chronic Fatigue Syndrome (ME/CFS)
- Glutamate – One More Piece in the Chronic Fatigue Syndrome (ME/CFS) Puzzle? The Neuroinflammatory Series Pt. II
- Does A Rare Neurological Disorder Provide Clues to ME/CFS and FM? The Neuroinflammation Series Pt 3
- Scared Stiff? Exploring Anxiety, Autoimmunity and Infection in Stiff Person Syndrome – A Possible Model For Chronic Fatigue Syndrome
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I believe the book “Stop The Thyroid Madness”, and the web site, by J. A. Bowthorpe, is a much more plausible scenario, than this report!
Especially for those with low body temp. that never get a fever!
Did you find that working with the thyroid helped you and if so how much. I think fever is actually not that common in ME/CFS.
overheating has been a problem – yet on the other hand I can’t stand to be cold. I have night sweats.
Thyroid med was high for a long time – 150mc but now reduced to 100 ms – don’t seem to have any adverse effect from that reduction – except am headachy – with onset of winter I am cold and achy and go to bed early.
I long to feel better – too many things – arthritis since young in my early 20s – having back manipulation under anaesethetic at 21 which possibly contributed to the arthritis. I’m now 72, have been hypoglycemic, also Fibromyalgic and Myalgia Ensephalmyelitis these latter years.
Pretty active even so – can’t sit and do nothing, so I love to potter in a small garden; also visit friends that have moved away – I keep adding to my circle of friends and they become very precious to me as we all are getting older.
I organize a support group locally for ME/CFS: not that I feel I know what and how but thankfully there is good info arround that I can offer to help people get some idea of the illness and that they are not alone.
Funny how so many of us do our very best to take care of our health; even to the point of being fanatical in taking care of what to eat, to avoid chemicals and dangerous food addititives etc.
Sadly though I see the same eventuality – people smoke, drink , have over indulgent lifestyle but we’re all going to come down with some weakness that will probably contribute to our death. “No get out of jail free card.” Thanks for your info – I will publish it in my travels as I met fellow sufferers and hope it can answer some of their fears etc. Cheers K
Oh dear. All the ME advocacy has been lost on Marco. He’s clearly not listening. If this is true, then I haven’t got CFS…oh wait, I haven’t, I’ve got ME. I don’t identify with the illness he’s sort of describing here but then, he’s not really clear on which set of patients he is describing. That seems to be his point but then what’s the point in defining any illness? It doesn’t seem that important to him but it is to me. I have Ramsay defined ME. That description describes my illness the best. Only today, I was thinking that I don’t have fatigue or poor sleep and the CFS diagnostic criteria mean that a lot of people get the diagnosis, who don’t have the disease, ME. Getting sick of the damage the vague criteria has done to research cohorts. Throwing money at mixed cohorts is pot luck. Hoping something will break through but this kind of article makes me despair.
For me what Marco is suggesting researchers take a broad look at all kinds of disorders that effect the brain and see if a central theory can connect them. He started off with the idea that sensory gating problems may better define ME/CFS or at least provide a better pathway to what’s going on and then noticed other disorders that have similar problems. It turned that there were quite alot of disorders that did, some of which we may associate with ME/CFS (FM, IBS, autism, ADHD) and others that we don’t (epilepsy?, schizophrenia). What might tie many of these disorders together? GABA/Glut…I forget the name! imbalance.
I think work on a better definition for ME/CFS must continue. (It is interesting, though, that the more specific you get with the definition the less it may bring in a representative group of patients.) If Marco’s right and these disorders do share some common pathology then that pathology should be uncovered in each of them at some point anyway. I assume something like that happened with the Common Disorders Group….researchers in different fields began to notice similarities were beginning to pop up and they popped up enough that they created a large study with all the different disorders in it.
I think the point, for me, is though – that those researchers were looking across disease boundaries and making connections. I don’t think we’re at that place yet but Mark’s blog suggests to me that it really is good to, from time to time, tear down disease boundaries and start looking anew.
So I agree that we don’t want to get rid of definitions and we want better one’s but what we really need are the studies that find the kind of biomarkers that the Common Disorder group found. We need to get away from the symptom-based definitions as fast as we can. After hearing recently that researchers in other disorders are finding that one symptoms can arise from many different conditions (ie diabetes can be caused by a number of conditions) I think its really important to go after the markers that differentiate. Who knows what we’re going to find. ME/CFS could be turned on its head. In fact I assume at some point it will be…
I think the real point should be no more subjective symptoms to define a condition: “fatigue”, “pain”, “malaise”, “brain fog”. I don’t really care what direction things go in as long as there are objective markers to provide legitimate comparisons between research studies.
I am not sure where Marco has been but the problem over the last 30 years is a group of psychs running wild with “outside the box” thinking trying to link all neurological problems to childhood trauma or poor behavior. Do we really want to encourage more of this crap?
In an ideal world with top researchers at NIH and world class researchers on the case l might be persuaded. Instead we get laughable funding of which a good portion goes to CBT nonsense with a few decent researchers overwhelmed by people who would otherwise be pumping gas if they didn’t have the luxury of doing fruitless research on tired Atlanta housewives.
It seems overly optimistic to think that any major answers are going to come any time soon. I would prefer going down a path that rigidly defines people into tight little boxes. At least there is some hope that people in these boxes could be recognized and there might be some chance at relieving symtoms and making things a bit more tolerable.
We share the same goal floydguy.
I’ve spent 28 of the last 30 years ill with no effective treatment at all offered.
Yes, over that time (especially in the UK) we’ve seen the BPS approach dominant but I’d suggest this is less to do with whether or not case definitions allow for the inclusion of ‘symptoms’ such as anxiety or depression and more to do with certain researchers having fixed ideas that ME/CFS has no organic basis (or at least none worth treating) and interpreting everything through that lens.
On the other hand, over the same period, I’ve witnessed a succession of ultimately failed attempts to identify a single pathogen with other researchers apparently convinced that one must exist if only we looked harder or had ‘better’ cohorts. In the meantime we still have little real understanding of the core pathology and still no treatments. Infection can cause fever and in some cases fevers can be fatal. Do we neglect to treat the fever because we haven’t identified the exact virus that triggered it?
I’m more concerned with identifying and treating the underlying pathophysiology as a priority without worrying too much at this stage what initially triggered it.
Re the case definitions the problem is that ‘symptoms’ such as anxiety or depression are named and conflated with conditions. So you exclude patients labelled with depression or anxiety despite the fact that ’emotional lability’ is a key symptom of Ramsey ME and both symptoms are pretty much the norm in other neurological disease.
Why not exclude exercise intolerance as its also found in mitochondrial disease and autonomic neuropathy to name a few or perhaps exclude PEM as MS symptoms are also exacerbated by exercise.
And then Leonard Jason finds that tighter case definitions not only identify a smaller number of patients, poorer functioning but also a higher level of ‘psychiatric’ symptoms despite the supposed exclusion of these symptoms.
Should this be a cause for concern? Not to me as that’s exactly what I would expect from the type of neurological condition I’m outlining and I’m also pretty sure that my own level of functioning would be enormously improved if I didn’t have to deal with the constant high levels of anxiety that are as likely to knock me off my feet as physical exertion.
The problem of defining ever tighter little boxes – without having identified the underlying pathology – is that you may end up excluding symptoms (and hence patients) that you consider ‘unrepresentative’ but that may be key to finding that underlying pathology.
Do we really know enough at this stage to rigorously define who should be in or out?
Maybe not but when your brain is so open it can fall out. If you’re looking at everything you’re looking at nothing.
The other problem is that when you decide to include everybody you’re also doing a tremendous dis-service to those who are put in the “Medically Unexplained” box out of convenience. It seems entirely likely that many people end up in the “CFS” waste bin because they have inconvenient symptoms/dysfunctions not conducive to 5 minute MD visits and expensive medications and profitable surgeries.
So what you get is potentially millions of people that have treatable things such as celiac disease, auto-immune conditions slapped with the label “CFS” because it’s economically beneficial under the guise of “let’s not leave anybody behind because they might have”CFS” – whatever that might be.
I have been listening. I just haven’t been convinced that this is a productive way to go.
I don’t have fatigue either. I actually thought that what I was describing was a neurological condition more akin to Ramsey ME than ‘chronic fatigue’ but perhaps that hasn’t come across clearly enough.
What I do suggest though is that the same neuroinflammatory state will show up differently in each individual leading to a wide variety of symptoms (and diagnoses).
In this context who decides what should be included or excluded from a strict definition that unambiguously defines ‘ME/CFS’ as discrete and separate and avoids overlap with other ‘discrete’ conditions.
Is this a useful approach when ‘overlap’ is increasing seen as the norm with shared biological underpinnings?
“Maybe not but when your brain is so open it can fall out. If you’re looking at everything you’re looking at nothing.”
I’ve also no intention of having a mind so closed it atrophies to the size of a walnut (if it hasn’t already). 🙂
I didn’t think I was proposing looking at everything. In fact I proposed that relatively rare sensory gating deficits might be a better pointer to the underlying pathology than much more common symptoms such as fatigue and pain.
We do agree though that CFS is a wastebasket or dumping ground. Where we appear to differ is in the notion that included within this wastebasket is a small group with ‘true ME’ and that ever more rigorous criteria will eventually isolate these patients for the greater good of all concerned.
May be. But I was under the impression that the term myalgic encephalomyelitis was coined in the aftermath of the Royal Free outbreak. I’m at a loss as to what rigour then went in to determining that prior and subsequent outbreaks such as Iceland Disease, Tapanui Flu, in Incline Village etc were also examples of ME and not similar but isolated and unrelated examples of various post viral encephalitis epidemics.
You could even suggest that the only cohort that should warrant a diagnosis of ‘ME’ is the original Royal Free one.
No I think I am more concerned that you prefer to frame this in psychiatric terms. When discussing Alzheimers or Parkinsons, one is unlikely to hear that the cause of “neuroinflammation” is depression, childhood trauma or poor behavior. But with “ME” or “CFS” any abnormalities associated with the ANS or “neuroinflammation” are immediately blamed on the patient.
I don’t really think we can determine who has “ME” and who doesn’t. I am only suggesting that research and patients be assigned to categories of known problems. That isn’t to say that there must be a Chinese Wall between patient groups.
Take mold for example. Some people including me are clearly affected by it and want to hear as much as possible about what is helping others. On the other hand there are people who get the DTs when mold is brought up.
Additionally, I have little problem walking upwards of 8 miles a day. In fact, I deteriorate quickly if I I don’t maintain activity levels. However, I am completely unable to exert myself for 5 seconds. I am sure there are a lot of people out there who just as soon not have me in studies geared towards GET.
I didn’t think I was pushing things in a ‘psychiatric’ direction but if I was its in the direction of a psychiatry that describes psychiatric and neurodegenerative conditions in biological terms. Unfortunately there’s not much I can do about the legacy of old school psychiatry in ME/CFS that falls back on vague notions such as illness beliefs and childhood abuse (the latter I feel is an old fall back often invoked when the researchers haven’t any better ideas).
Please bear in mind that the conditions I suggested might share the same neuroinflammatory state as ME/CFS included ‘mood disorders’, psychiatric disorders and degenerative ones such as dementia/Alzheimers, Huntingtons etc. The reason I’ve been discussing anxiety and depression more than Alzheimers for example is because they are readily recognised and measured by questionnaire whereas the evidence for cognitive deficits in ME/CFS is largely mixed. Dementia will feature prominently in Part V though (yes there is more I’m afraid).
I also have to say that folks with Alzheimers or Parkinsons aren’t immune to the joys of CBT and ‘rehabilitative’ exercise either.
On that subject I agree that exercise intolerance, while far from unique to ME/CFS, is (outside of deconditioning which I think we can all agree is not the primary problem in ME/CFS) sufficiently unusual that it should provide major clues to the underlying pathology if it was fully investigated and documented.
Diabetes related autonomic neuropathy is one condition that features exercise intolerance. You might find the following paper interesting as it discusses the precautions needed when attempting rehabilitative exercise programmes with these patients (the symptoms and physiology will probably be familiar – reduced heart rate variability, resting tachycardia, prolonged QT intervals etc) :
Well I guess that is crucial area where we disagree. I don’t suffer from “mood disorders” but do suffer from cognitive deficits (neuro-psych testing). When you bring “mood disorders” into the fold you open up the discussion to endless babbling about “mind-body” nonsense. Personally, I think it’s much more productive to focus on the exercise intolerance or other “objective” markers.
This is another reason why I am not such a fan of opening up the definition to every symptom because it’s too easy for the focus to get narrowed down to the lowest common denominator – which has what happened already (fatigue). You seem to be advocating that it be shifted to “neuro-psych” issues which I don’t think would be any improvement. Simon Wessley and the DSM 5 crowd I am sure are drooling at that prospect of endless income researching and “treating” patients.
Frankly I don’t get it. Haven’t we tried the cum baya definitions for 30 years now? Can it get any more nebulous than it already is? And for heavens sakes just say no to questionnaires. Questionnaires are the domains of psychs, “CF” researchers and other snake oil salesmen. I no longer fill out questionnaires. At that time, there is objective proof on neuroinflammation from fMRI than great but I am not buying into it based on questionnaires.
Thanks for your thoughts though. I don’t mean to be overly argumentative!
I appreciate you’re not just arguing for the sake of it – far from it. I don’t expect you to agree with me and I could be very wrong.
Simply I’ve come to the conclusion that the same neuroinflammatory process underpins a wide range of neurological disorders including those that were previous considered psychiatric or mood disorders. The science increasing supports this notion. I’m sure we would both agree that ‘ME/CFS’ has at least a neurological component?
As various parts of the brain may be affected and the process may interact with factors such as genetic predisposition or environmental ‘insults’ then the same process can result in a wide range of symptoms whether they are cognitive, movement, sensory or indeed mood. Not everyone will have the same mix of symptoms. I have had and still have symptoms which could be classified as ‘mood disorders’. I don’t have much by way of pain thankfully but I do have sufficient symptoms to meet at least the CCC case definition.
With another mix of symptoms I may well have been classed under one of the other labelled conditions in fact as stated in my biog – the depressive and bowel ‘symptoms’ ended up with me labelled with the ‘conditions’ of depression and IBS.
Its merely the fact that we don’t easily fit into these other labelled categories that has resulted in us being given the default label of ‘CFS’ -hence why I suggested that this is not a discrete illness in any concrete sense. Given our cognitive deficits I wonder how many of us would have been given a label of dementia if we’d been in the right age band?
The problem with ever more strict definitions that try to avoid overlap with other labels is that this risks excluding some symptoms that point in the direction of neuroinflammation.
I really can’t see why cognitive problems are good and ‘mood’ are bad? Both are intrinsic to neurological conditions and I was trying to highlight that fact.
OK – I am fully aware of the historical and current background re the interpretation of these things but we can’t carry on continuously on the defensive especially if its counterproductive.
That’s about as clear as I can make it.
PS – ‘Mood’ will feature less from now on – bearing in mind these blogs started with sensory gating measures – objective measures of cognitive function – and that’s where they’ll end.
All the best.
Again I actually don’t disagree that there probably is a lot of overlap with the neuro-psych illnesses. I just don’t want the comparison done on the basis of questionnaires.
I’ve been a patient of Shoemaker who has diagnosed me with CIRS which is Chronic Inflammatory Response Syndrome. Shoemaker is a bit off the reservation but I appreciate his focus on inflammation being a core issue. And I really appreciate the fact that he has attempted to establish objective criteria as the basis for the diagnosis.
At least he has put himself out there suggesting that if you have high C4a, TGF Beta1, MMP9, low VIP, low VEGF and a handful of other tests you’ve got an inflammatory response problem.
The “CFS” researchers are still stuck at if have fatigue than you have a some kind of mysterious problem that is way too hard to figure out and needs more research.
I think I’ll take option one for now.
Thank you Marco and Cort.
I think the common thread between all of these diseases and disorders Marco is discussing is the “kynurenine pathway”. The up-regulation of this pathway produces toxic metabolites that are involved in depression, bipolar disorder, cancer, Alzheimer’s, ME/CFS, fibromyalgia, IBS, glutamate and GABA imbalances etc.
The kynurenine pathway is a tryptophan degrading pathway that can be upregulated by cytokines such as tumor necrosis factor. Tumor necrosis factor is elevated in all of the diseases Marco mentioned.
I completely agree with Marco’s central theory. These diseases share the same symptoms because they share the same underlying disease pathways. The up-regulated kynurenine pathway is just one pathway they all share though.
Thanks for the link and the comments Annesse.
This kynurenine pathway isn’t something I’ve come across during this process but its good to see that there may be another shared biological pathway (and perhaps another level of complexity).
From what I remember, tryptophan issues could cause ‘central fatigue’; ie brain mediated fatigue and I look forward to checking it out. Thanks for the link. 🙂
Hello again Annesse
I just realised that I had been reading about the kynurenine pathway in a very dense but excellent paper called Neuroinflammation and psychiatric illness. I hadn’t made the connection until I started re-reading it this afternoon.
This pathway appears to be part of the mediation between astroglia and microglia and hence the proinflammatory (TH1) and anti inflammatory (TH2) expression of cytokines in the brain (the TH1/TH2 see-saw) and in the process determines (and is determined by) extracellular glutamate levels and re-uptake.
Well worth a read
Cort, have you engaged psych conditions as a result of studying neurotransmitters? Psych conditions appear earlier in life, and do not have hard signs of a physical condition, ie. swollen painful glands, sore throats, etc. Definitions do not obscure, but offer guidelines. The future of genetic studies will unlock many questions facing patients, physicians. There is quite a difference in past and present blood and other tests, when compared to ‘behavior only’ appoach of psychiatry. I am sure there are patients who do present a crossover picture in proper diagnostic manner, yet there is no co-morbid illness, as people do die from me/cfs alone. Do you believe in glutamate supplementation? I truly feel it takes a team approach to treating me/cfs, as many need psych evaluation when overwhelmed with a life changing loss that occurs. Now, they are throwing out the DSM5, an unfortunate change in timing. I believe change is coming, and for many. Yet, admire your writing as it reflects a futuristic slant, by comparing and involving many conditions.
I was really surprised to hear on NPR that there is not a single biomarker for any ‘psych’ condition. That was attributed to the difficulty understanding what’s going on in our brain matter. The news wasn’t particularly good with brain disorders in general; they’ve poured hundreds of millions of dollars into some of them and are making real progress in some but finding biomarkers has been difficult.
I like the big data approach that Kogelnik is taking – trying to enlist 100’s or 1,000’s patients in studies and then digging into molecular or genetic basis of this disorder. I sincerely hope he can do that.
The DSM5 seems to be getting flack from all sorts of directions.
My experience: There is hope. The breakthrough for me was the CORRECT INTERPRETATION of my Yasko Comprehensive Liver Methylation DNA test (get the $79. special at 23andme.com if you want a less expensive report) and understanding that, after four decades or more of investigating every approach available to me after being born with epigenetic injuries, that all mitochondrial diseases have certain inflammation processes/patterns in common.
Finding these environmental toxicity factors that aggravate inflammation and remedying them with the DNA-appropriate food, water, supplements, household items, a chemical-free environment (as much as possible) is essential to my healing. –Meditative spiritual perspectives and practices too. One can still be sheltered with a CFS/CFIDS/Lyme/REDD diagnosis for insurance purposes. But that perspective is way too small for our real-time daily individual efforts at self-healing; we will not heal quickly if we leave all direction/decisions to our doctors; not even the best doc can keep up with the info overload and each must stick with their chosen research direction. Many roads and research directions are converging at this point — if you follow your gut, also essential for healing, and connect the dots and file them away for further reference. Being a fired-up healing warrior also helps, if this is undergirded by compassion action for the entire planet’s environmental toxicity crisis. Yeah, it does take that, and it is also part of the healing element.
Untreated Lyme/CFIDS and a lousy D.O. led to my thyroid removal (gory details left out). Stop the Thyroid Madness book and website are likewise essential; all the conventional endos and other specialists utterly failed, even after thyroid removal. Lifelong antibiotics were also part of the iatrogenic injury pattern (the info-control Industry, not the good-hearted docs except for one or two, is responsible). Integrative and energy medicine and and decades of research of record-keeping and research allowed me to live much longer than my mother.
Unknown to most, half or more of all Caucasians, Hispanics, African-Americans and perhaps other groups have broken components to their MTHFR gene pair and its variations; this shows up on both DNA tests; this is key to wellness, especially emotional/immune wellbeing. Discerning and measured involvement with primarily “Biomed,” not Big Pharma med, has saved my life. Still in process, I have just done things I never dreamed of before and will continue to do so.
I have been doing research myself on the balance between Glutamate and GABA. My primary issue is HyperPOTS – which includes high levels of NE (norepi) upon standing. I have started to wonder if there isn’t a connection in the different types of POTS and an imbalance in these two neurotransmitters. In POTS there is an imbalance in the sympathetic and parasympathetic systems of the autonomic nervous system. People can have extremes in both directions and sometimes have dysfunctions with both at varying times of the day. If you think of the sympathetic system as the action part of the nervous system you could compare it to what glutamate would do in the body. Then if you look at the parasympathetic and the calming part of the body that could be connected to the GABA neurotransmitter which is calming. The interconnections of these two and the fine balance that needs to occur in the body could swing one to extremes in either direction if the conversion of this doesn’t happen properly.
With all the study going on with methylation and the different pathways and what is required to have the conversions happen properly – if there are gene mutations that affect the proper functioning of this system – then you have some of the issues that Marco is talking about. You could have problems with CBS and BHMT pathways and that can mimic problems with COMT pathways. Then you’ve got a whole lot of body dysfunctions happening. Not to mention the connections that foods play in this. If there is a CBS mutation and issues with proper sulfate/sulfite metabolism and you also have issues with glutamate – these are two things that can be addressed with diet. And a diet high in either with a problem of conversion and/or assimilation could intensify your symptoms – with the next meal you have.
I tend to agree with Marco. If there are genetic mutations and epigenetics at play here – and we can figure out what and where they are and what dysfunction they are causing to the body —we might get down to the core issues. Now, whether or not we can figure out concretely how to get around these mutations and tweak our dysfunctions either with diet or supplements —will remain to be seen. But, there are several doctors working on theories and putting that into practice with their patients and many are finding great results with this. I’m still in the learning phase of this and have barely scratched the surface here. But, it is very intriguing to me and makes sense.
My personal thoughts on POTS, ME/CFS is they have very similar – yet different – presentations and there may be the same basic underlying core issue – with different presentations. But, probably the main thing is a dysfunction of the immune system, inflammation and ultimately genetics.
Any time someone has an “out of the box” theory – there is going to be criticism because others have their own theories. I tend to be one of those that will look at other angles and I get lots of criticism of my ideas too. But, the ideas come from a lot of research that we have in our minds – it will take time to explain what all we’ve learned with our research. Give him time to build on what he is thinking. Don’t be so fast to condemn an idea just because it’s not along your lines of thinking. All the things considered “Facts” of today were yesterdays “Ideas”. Thank goodness for those that will think “out of the box” (and have the courage to talk about it), because if the angle that is being pursued by the majority – isn’t working —at least there will be another direction to head off in.
Kudos, Marco – we need the “out of the box” thinkers!
Many thanks for the kind words – and very eloquently put too.
The autonomic nervous system is coming up next in the discussion which might be of interest.
Food is definitely an issue for me. I do love my food but it doesn’t love me and I feel much more symptom free when I eat little.
Apparently ‘early satiety’ is a sign of autonomic dysfunction and small regular meals are better tolerated.
I was wondering -i also have POTS- if high levels of NE (norepi) is compensating for lack of energy? Or is this respons pure dysfunction? that is a very important issue. I do not know the answer. Anybody have an idea?
High NE could very possibly be a compensation to improve blood flow. When your body releases NE it causes your veins to constrict and that therefore will improve blood flow back to the heart and to the brain. Many/most doctors and patients alike try to suppress NE release because that could cause those adrenal type surges that we feel that causes a sort of anxiety/panic attack feeling. If this is truly a compensatory thing and the bodies way of trying to increase the blood flow to these important places and we suppress this —question is – will this make us even worse? (Since, I’m an “out of the box” thinker —this is not the direction or idea that the majority of POTS people think. Most just want that feeling to go away.) There are a few of us experimenting with ourselves to actually increase NE levels even more and have our bodies uptake it better with a more level release or uptake- to see if an increase to the body will stop the surges. If there is a more constant level to the body and it goes into the cells better will this improve blood flow and stop the surges? We will see.
We’ve always thought of our high NE levels as “dysfunction” when in actuality it very well could be our body reacting properly to what is happening with blood flow issues. Whether or not this is “causing” low energy – not thinking so. Because NE increases energy – but, could with the long term release tire out the adrenals. The adrenals could be tired from constant compensations. But, there again there could be an imbalance between glutamate (stimulatory) and GABA (calming) neurotransmitters and those could have the same effects on the psyche with energy vs. tiredness. We seem to be getting closer to answers, but personally – I think – we have to look in a different direction than is most commonly looked at.
Thank you Issie. NE also push up the level of glutathione and suppress the TH1 (NK etc..) in favour of TH2, found in ME. That can explain the ”constant low grade of infection”. I think that there is one organ overlooked in ME, that is the liver. The liver produces glutathione and many patients became sick with EBV. It is very difficult. Maybe we will never know what this disease realy is about 🙂 But i think that the POTS group is more homogeneous and objective than CFS.
Would you know which kind of blood test could be taken to test Glutamate levels?
I would like to get tested on those, as well as my brother. In his case He came up with a PET scan with white spots in the frontal lobe, and they think that it could be the beginning of a dementia, but I heard that glutamate can cause this kind of damage as well in the brain, but I would not know which kind of tests we should order in the lab to check this…
Thanks in advance
Sorry to hear about your brother.
I’d be very surprised (but happy to be told otherwise) if glutamate blood levels can be measured accurately or indeed would correlate to brain glutamate levels which vary anyway depending on the brain region studied.
In a research setting – for example in this paper examining extracellular glutamate levels in multiple sclerosis :
– magnetic resonance spectroscopy is one tool that can be used ‘in vivo’.
I would imagine though, if dementia is suspected, that any diagnosis would be based on clinical history and various cognitive tests rather than measuring neurotransmitters.
Hope this helps.
Some of us with POTS are finding that there are auto-antibodies to GAD65, causing the body to not convert glutamate to GABA. There is a blood test to check for this. Mayo Clinic has an auto-antibody panel test that checks for this along with some other things. I found an article written by a person who it was connected to diabetes, autism, autoimmune problems, neuroinflammatory problems, and some neuro type diseases like Stiff-Person Syndrome. Here is the link:
Here is an article connecting this to chronic pain and an epigenetic suppression of GAD:
Here is one auto-antibody test available at Mayo that includes this test. Note that it indicates cancer (don’t let that scare you) but of neurological problems of unknown etiologies.
Hopefully, this will give you a place to start looking closer at this.
“Some of us with POTS are finding that there are auto-antibodies to GAD65, causing the body to not convert glutamate to GABA.”
Really interesting Issie – thanks! I wonder if many ME/CFS doctors are testing for this?
”I suggest that an abnormal balance between glutamate and GABA underlies all these conditions and that high or low glutamergic states can be found, at times, even in the same disorder. ”, I do not agree and it make no sense, sorry. Post viral ME can not be explained by thios theory. I think the low glutamate is due to a constant state of infection, toxins etc…. Only an overactive autonomic nervous system can explain everyrhing. But what drives this ”overdrive’, that is the central guestion in this disease.
I don’t see why not Gijs?
Although I haven’t spoken too much to date about etiology I will and I’ve already previously described examples of conditions characterised by a GABA/Glutamate imbalance arising from a viral or autoimmune onset plus the possibility of a self-sustaining ‘feed forward’ neuroinflammatory cycle.
I agree that the autonomic nervous system is a critical part of ME/CFS.
I’ll be discussing how this model might impact on autonomic function in the next blog.
Perhaps later today.
But, then you have to determine what causes the autonomic nervous system to malfunction. What is the core issue here?
I’d say that number one would be genetics and then autoimmune issues and closely connected to that is inflammation. See what we can do to affect those things —ie. epigenetics, autoimmune support and anti-inflammatory aids. And along with diet –that I feel will work on all these levels —then see what we’re left with. Once we change the things we can change — DIET. Work on our lifestyle and any stresses we may have that can be eliminated. Support the immune system. Work on the “core” issues. The only other thing available would then to be to treat the left over symptoms. At that point it’s a Band-Aid approach. But, it may take that to have the best quality of life that we can. It’s not so much about quantity —but quality.
The main thing is No changes = NO CHANGE. There has to be changes in what we do and how we do it —-or we’re just left with the way things are.
Thx Marco for your response. I look forward for your explantion what drives the ANS problems. One question: what causes the abnormal balance between glutamate and GABA? Is this genetic, acquired etc? By the way i have no problems with your theory if it would be correct. I just look for the tryth just like anyone here. But we all do not know the cause at this moment. In your theory the liver which produces glutathione can be the problem especially post viral EBV.
The evidence for me suggests (as regards the onset of ME/CFS) many potential routes leading to this state and I hope to set out ‘theoretically’ how a GABA/glut imbalance might fit this model.
Dear Marco. I think it is important to keep an open mind to all hypothesis – even though it might be “ a controversial and potentially unpopular proposal”. We must never believe that we have “the truth” about anything in science. I’m actually a little tired of the discussion about diagnostic criteria and disease term. In stead I would like to see some systematic and thorough research – using latest technologies.
Instead of focusing on what we shall call the disease, we must determine the different biological profiles in each patient:
An immune profile: Cytokines, NK cells, T reg cells, and so on.
A profile for autoantibodies including autoantibodies previous found in orthostatic intolerance and POTS.
And as you suggest a neurotransmitter profile (Levels of glutamate, GABA and…?), and I will go a little further and look into TRP ion channels and interaction (cross-talk) between neuropeptids /neurostransmitters /cytokines/metabolites.
Please look at these figures to understand my idea
Figures are from this article: Importance of TRP channels in pain: implications for stress http://www.ncbi.nlm.nih.gov/pubmed/23277035
Technology about TRP is emerging: Systematic and quantitative mRNA expression analysis of TRP channel genes at the single trigeminal and dorsal root ganglion level in mouse. http://www.ncbi.nlm.nih.gov/pubmed/23410158
These profiles (and more that I have not thought of) should be taken before and after exercise. And then we can call the disease “a profile combination number” instead of a name. :-))
Best regards Helle
References to autoantibodies in ME/CFS, orthostatic hypotension and POTS:
Reduction of [(11)C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor http://www.ncbi.nlm.nih.gov/pubmed/23240035
Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome http://www.ncbi.nlm.nih.gov/pubmed/12851722
Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome http://www.ncbi.nlm.nih.gov/pubmed/19623655
In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation http://www.ncbi.nlm.nih.gov/pubmed/23664637
Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an “autoimmune” orthostatic hypotension http://www.ncbi.nlm.nih.gov/pubmed/22130180
Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism http://www.ncbi.nlm.nih.gov/pubmed/22215709
Postural orthostatic tachycardia syndrome: the Mayo clinic experience http://www.ncbi.nlm.nih.gov/pubmed/17352367
Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome http://www.ncbi.nlm.nih.gov/pubmed/23002038
Autoimmunoreactive IgGs against cardiac lipid raft associated proteins in patients with postural orthostatic tachycardia syndrome http://www.ncbi.nlm.nih.gov/pubmed/23562385
Thanks for all the references. If we work on the auto-immune system and get it work properly —might we correct so many of our issues? Might that bring some of these other things into balance? That’s the approach I’m taking and I’m having some noticeable improvements.
More reading to do I think!
Interesting that the recent finding of a shared biological underpinning for a number of ‘psychiatric’ disorders as mentioned above also involves a channelopathy :
“The consortium found specific single nucleotide polymorphisms (SNPs) common to all these conditions particularly calcium-channel activity genes”.
Have they been able to identify any particular diseases/disorders linked to TRP channels?
Not a particular disease that ONLY involves TRP. But TRP function is involved in many diseases.
Transient Receptor Potential Cation Channels in Disease
And agonist and antagonist for different TRPs can be utilized as drugs. TRPs are targets for treatments.
Targeting TRPs in Neurodegenerative Disorders
I think ROS, metabolites and lack of glutathione is a problem that affects TRPA1 in ME/CFS.
Hi Marco. I read your article yesterday before any comments had been added, and have spent the day thinking about your proposals. Thank you for stirring my brain cells. I can’t pretend to understand even a fraction of the technical biological research that is going on (although I keep trying), nor attempt to evaluate the different claims for importance that each approach puts forward. But it is obvious that we have to consider other approaches, and that closing our minds to them without evidence is risky. Unless people like you challenge the common approach and make us think critically about our assumptions, following the trend may not lead us anywhere.
From purely a logical rather than biological point of view, the obvious approach would be not to choose either the tightly-defined ME route (if we could all agree on one), nor the catch-all definition to find a common “cause”, but to use a three-tiered study group of patients. The control group should be healthy, of course. A second group, perhaps, should fit the strictest, classic, infection-prompted, post-exertional fatigue definition of ME. But there should be a third group which fits into a broader spectrum but which does not blur onto the second group. In other words we should consider three distinct groups, with no fuzzy areas between them. That also means that we should make more use of the severely affected: there is no point in considering patients who are already close to the standards we set for being “healthy”. That way it would be possible to determine whether factors are specific to the classic ME patient, or if they are shared by many. Following success here, we could then extend the study.
I did once track (superficially) through all the research papers on ME from 2000 to 2011, and I can only remember a very few having three groups, however defined.
It would not be right to take a large group and divide it up into subgroups (as PACE did), simply because there will be too many people in the fuzzy areas of overlap. For clear results we need clear separation of subsets by design from the start.
Its good to think 🙂
For a long time I was also convinced that ever tighter definitions were the way to go and in the past probably argued vociferously that that was the case. It was the process of working through this blog series that convinced me that this approach also has its dangers?
I agree that a mixed approach may be the way to go. As i said in the blog ‘lumping’ and ‘spitting’ may have complimentary benefits and in fact this is increasingly happening with sub-groups being identified but also cross cutting research such as Newton’s comparisons with fatigue in primary billiary cirrhosis.
I do appreciate a well reasoned argument 🙂