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.  

Abstract painting

Could trying to strictly define ME/CFS obscure more than it reveals?

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’).


Does an out of balance GABA-Glutamate system tip the scales in ME/CFS and other disorders.

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.

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.


The Cross Disorders Study finding that a gene exerted powerful effects across a variety of different disorders suggests that symptoms are not a good guide to physiology

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.


Too much ‘splitting’ in ME/CFS could obscure fundamental processes occurring in the disorder.

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

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