Myalgic encephalomyelitis: International Consensus Criteria, 2011, Carruthers et al

[Andy]

Abstract

The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3).

Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria.

The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

Open access

 

[Andy]

Given that there is a range of support for and criticism of this criteria spread around various discussion threads I thought it would be useful to actually have a specific thread for it.

 

[Peter T]

@Andy, thank you for posting I had thought I should read up on this but not got round to tracking the reference.

 

[Evergreen]

I came across this during the week - Maclachlan et al. 2017 (incl. Jason & Newton) explain some of the problems they see with the ICC:

The possibility that current criteria include symptoms that are not primary features of CFS, specifically in relation to the Canadian 2011 criteria which encompasses a broad spectrum of symptoms across body systems, and confounds clinical presentation and research, must be considered. The number of symptoms across many physiological symptoms included in the Canadian 2011 criteria may mean that, rather than diagnosing a more severe CFS phenotype, these criteria capture both CFS and other co-morbidities with non-specific symptoms. This may not only affect management and subsequent prognosis, but also give rise to an inaccurate and confused picture of which condition (or conditions) is being researched and serve to exacerbate the stigma associated with the condition.

Furthermore, it is possible that the inclusion of more widespread pain with or without hyperalgesia in the 2011 criteria may be a confounding symptom–particularly in view of the association between pain and both autonomic dysfunction and cognitive impairment (attention, psychomotor speed, verbal and working memory)[40–42].

 

[Andy]

I want to double check with the forum hive mind that;

1. inflammation of the brain and spinal cord has still not been proven?

2. a pathological inability to produce sufficient energy has in fact been disproven? Or is this still in the not yet proven category?

 

[Jonathan Edwards]

I want to double check with the forum hive mind that;

1. inflammation of the brain and spinal cord has still not been proven?

2. a pathological inability to produce sufficient energy has in fact been disproven? Or is this still in the not yet proven category?

Standard MRI very simply rules out inflammation in the standard sense, of clinical significance. What have not been ruled out are subtle changes in behaviour of cells such as microglia.

Very strong evidence from CPET studies and more standard clinical assessment rule out an inability to produce sufficient energy being the main basis for symptoms. Certainly, CPET rules out such an inability being a defining feature of ME/CFS. Many people with ME/CFS have normal CPET studies at lest at day 1.

 

[PageofME]

Since Prof. Iwasaki and colleagues have published their brain fluid study in ME/CFS in July 2025 Prof. Scheibenbogen repeatedly has referenced their study to claim that brain inflammation was proved at last in ME/CFS.

https://archive.ph/Ig0bC

Iwasaki and her co-researchers claim that they found two heightened inflammatory markers. The classic cytokines and another moelcule called matrix metalloproteinases. They found particularities also in the plasma of ME patients. The most important claim of the study though is that based on the results of their brain fluid analyses there are two distinct immunological brain inflammation patterns in ME patients.

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals' quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes...

pubmed.ncbi.nlm.nih.gov

I think that there are many more studies and autopsies from the past decades that strongly hint at brain inflammation.

My guess is that Iwasaki and Co's findings will be reproduced soon in Berlin by Scheibenbogen.

Personally I knew that brain inflammation was a thing in ME since I became a moderate and felt that my brain was on a low-level fire. TO read in the clinical literature that in ME/CFS a special form of headaches or migrainic pain occurred was upsetting. In hindsight I think that the "mild" ME/CFS health level inflammation is contained to the immune system.

Research points to the origin of ME/CFS as a problem with the T-cells and the complement system (auto-immunity and HHV-6B are being researched as the cause). And then, when patients deteriorate – whatever is the cause of the ME inflammation process – it jumps to the brain as well.

According to a review that was published by the ME Association in 2019 damage to the mitochondria is only secondary and possibly caused by toxins from said inflammation process (Herpes researchers like Prof. Prusty have shown since 2020 that HHV-6B would be a fit). Sometimes I feel that the pandemic has led biomedical researchers astray, but they're luckily finding back into their tracks again.

MEA Summary Review: The Role of Mitochondria in ME/CFS | 13 July 2019 - The ME Association

This latest review looks at energy production, and the ongoing search for clues as to what might be causing problems in ME/CFS.

meassociation.org.uk

 

[Jonathan Edwards]

Iwasaki and her co-researchers claim that they found two heightened inflammatory markers. The classic cytokines and another moelcule called matrix metalloproteinases.

Inflammatory markers are not inflammation. They are simply things that are often found in association with inflammation, but also sometimes without inflammation. Inflammation is measured directly by things like MRI. And MRI shows there isn't any. I have no particular reason to think that Iwasaki really knows what she is doing. Most scientists who splatter their ideas on Twitter do not.

 

[Hoopoe]

2. a pathological inability to produce sufficient energy has in fact been disproven? Or is this still in the not yet proven category?

The evidence shows slight deficits or normal function. It is misleading to present this as defining characteristic of the illness.

 

[Creekside]

They are simply things that are often found in association with inflammation, but also sometimes without inflammation.

I expect that some claims of finding inflammation in the brain are merely incorrect usage of that word. Inflammation is more than vaguely "something to do with the immune system". Has anyone trained AIs to use the more specific definition?

 

[Yann04]

Very strong evidence from CPET studies and more standard clinical assessment rule out an inability to produce sufficient energy being the main basis for symptoms. Certainly, CPET rules out such an inability being a defining feature of ME/CFS. Many people with ME/CFS have normal CPET studies at lest at day 1.

I assume we can be quite confident this rules out a body wide lack of “energy” in the classical sense.

Does it rule out a local effect. Like lack of “energy” to a brain region or lymph nodes or bone marrow or something. Does what I said even make sense?

 

[PageofME]

Inflammatory markers are not inflammation. They are simply things that are often found in association with inflammation, but also sometimes without inflammation. Inflammation is measured directly by things like MRI. And MRI shows there isn't any. I have no particular reason to think that Iwasaki really knows what she is doing. Most scientists who splatter their ideas on Twitter do not.

I will check in with my radiologist and ask him whether he believes that subacute herpes brain inflammation can be seen in an MRI.

As a biomedical lay person with a degree in the arts neuroimaging techniques like MRI struck me as a very indirect way to look at something. Every clinical neurologist and infectiologist that I have talked to informed me that brain inflammation caused by a pathogen is accounted for by an analysis of the brain fluid.

I am therefore very happy that Jacqueline Cliff who is going after the HHV-6B causative hyothesis of ME/CFS has found out that DNA loads in saliva are a valuable source either. Because I want to start to do regular testings for HHV-6B next year with my specialist.

My impression of Prof. Iwasaki is very different of yours. I think she's excellent and its so important we have her. She has exactly this confidence to make up her own mind and a willingness to serve patients and not please her colleagues that allows her to initiate a study using brain fluid when no one has done it in ME/CFS for decades.

Your judgment of her using Twitter I find rude and inadequate for a scientific discussion. Also, I suppose, it is not her but her comms team that's on Twitter actually.

Last but not least: She's on the board of Roche now. Why would that be if Roche wouldn't think that immune therapy for ME/CFS could be their new cash cow.

 

[Jonathan Edwards]

I will check in with my radiologist and ask him whether he believes that subacute herpes brain inflammation can be seen in an MRI.

I just asked my radiologist (my wife). She says yes.

As a biomedical lay person with a degree in the arts neuroimaging techniques like MRI struck me as a very indirect way to look at something.

Absolutely not. Inflammation is most critically defined in terms of an increase in vascular permeability that increases tissue water content. Bog standard MRI measures tissue water content. It is as direct as you could have.

Every clinical neurologist and infectiologist that I have talked to informed me that brain inflammation caused by a pathogen is accounted for by an analysis of the brain fluid.

I don't think they meant what you might think. Analysis of fluid indicates migration of cells and leakage of protein through the brain into CSF. You have no idea where they come from - maybe brain, maybe meninges. MRI is much more direct.

I am therefore very happy that Jacqueline Cliff who is going after the HHV-6B causative hyothesis of ME/CFS has found out that DNA loads in saliva are a valuable source either.

You may be aware that I have recently published a paper on ME/CFS mechanisms with Jackie. She is certainly interested in the role of persistent herpesvirus but I am not aware that she thinks there is any brain inflammation. Saliva is rather a long way from brain!

She has exactly this confidence to make up her own mind

Hm. All I have heard from her are tired old tropes that people get taught in medschool. I agree that she has opinions but it is a pity that they are so stereotyped and outdated. I have heard nothing original.

Your judgment of her using Twitter I find rude and inadequate for a scientific discussion.

Sometimes it is worth calling a spade a spade. I have been in the imunology business a lot longer than she has and I have reason to think that I have made a more significant contribution to understanding of disease. (At least I can say that the spin off from my work runs into tens if not hundreds of billions of health care.) Has she actually discovered anything? Devised any innovative treatments? Do you have a reason for defending her based on output?

 

[Jonathan Edwards]

Last but not least: She's on the board of Roche now. Why would that be if Roche wouldn't think that immune therapy for ME/CFS could be their new cash cow.

The irony is intriguing. I had to persuade Roche to use rituximab in autoimmune disease. It took me nearly five years. I won't say more because I might be sued, but please don't take the actions of big pharma staff as based on great intelligence. We parted company because I complained that a death in my trial had not been included in the initial publication. (They previously chucked me off an advisory for pointing out that a drug's side effects would be indistinguishable from the disease it was intended for.) I have been in this business a long time

 

[SNT Gatchaman]

MRI is typically abnormal in HSV encephalitis, especially if clinically severe. It likes the temporal lobes, but may be asymmetric or unilateral. See eg for a severe cohort

Assessment of Magnetic Resonance Imaging Changes and Functional Outcomes Among Adults With Severe Herpes Simplex Encephalitis (2021, JAMA Network Open)

On the other hand, there's a high rate of normal neuroimaging in autoimmune encephalitis (esp. anti-NMDA receptor). I've seen a couple of such cases.

MR Imaging Findings in a Large Population of Autoimmune Encephalitis (2023, American Journal of Neuroradiology)

The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies.

Brain MRI Characteristics of Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Their Associations with 2-Year Clinical Outcome (2018, American Journal of Neuroradiology)

Twenty-eight (28/53, 53%) patients had normal MR imaging findings