WHAT CAUSES Myalgic Encephalomyelitis, CFS, "ME/CFS" or SEID ?
WHAT CAUSES Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, "ME/CFS" or "SEID" ? The latter three are "NOT" M.E.
WHAT DO WE KNOW? AND WHAT REMAINS UNCERTAIN OR UNKNOWN?
1. How the history of Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, “ME/CFS” and “SEID” (ME/CFS) has been defined — and how changing definitions and criteria have shaped and complicated research into causations.
2. Why did “separate” medical entities become erroneously “conflated”, whilst at the same time being “excluded”?
3. What group of viruses cause M.E.?
4. Should antivirals for enteroviruses using the influence of Hep C and HIV be developed?
5. Is M.E. an “Encephalomyelitis”?
6. Where is the NICE guideline for “Myalgic Encephalomyelitis”, when Leeds Teaching Hospitals have been sitting on the information for the need for one, since 2023 in their Microbiology Manual? Is a paradigm shift required for M.E.?
7. Is there a need for dedicated emergency inpatient services, dysautonomia clinics, and multidisciplinary neurological and infectious-diseases care — including neuromuscular and motor-disorder specialists — for people with M.E.?
8. What did the “original” 1988 Holmes “CFS” Definition overlap with?
9. Shouldn’t “ME/CFS” really be labelled “SEID” as the authors of the IOM/NAM Algorithm suggested, to differentiate it from Epidemic “Myalgic Encephalomyelitis, or M.E.” and the original Holmes “CFS” Definition?
10. Does the “SEID” (ME/CFS) Algorithm overlap with Long COVID?
11. Should IVIG, SCIG, PLEX and Ampligen be made available where clinically indicated for post-viral, persistent-infection, encephalomyelitis and autoimmune disease?
12. Predisposing, precipitating and perpetuating factors.
13. Current and future CFS (SEID and ME/CFS) research criteria study, whilst M.E.-specific research is not being funded on account of its cover-up.
14. Is it time for a statutory public inquiry into the failure of charities to accurately represent M.E.; its misrepresentation, mishandling, suppression and invalidation; the misinformation and disinformation surrounding it; its medical conflation with unrelated “fatigue”-associated illnesses; the exclusion, marginalisation and medical abuse of people with M.E.; the devastating impact on children with M.E. and their caregivers; the promotion of inappropriate treatments such as GET and CBT; the suppression and lack of funding of M.E.-specific biomedical research; the marginalisation of M.E.-specialist researchers and clinicians; and the influence of CFS, ME/CFS and SEID criteria developers with a vested interest in the criteria they themselves created?
15. Should there be an independent investigation into whether the GMC protected the PACE authors and other doctors, including GPs and neurologists, while subjecting Dr Sarah Myhill to retaliatory regulatory action after she reported them and challenged NICE and NHS medical policy affecting people with M.E. and misdiagnosed CFS patients as a whistleblower?
CONTENTS
3 - BACKGROUND
4 - HOW THE HISTORY OF "M.E. and CHRONIC FATIGUE SYNDROMES" HAVE BEEN DEFINED AND COMPLICATED RESEARCH INTO CAUSATION
7 - "LONG COVID" OVERLAPS WITH THE "SEID" (ME/CFS) ALGORITHM
8 - WHAT CAUSES "CHRONIC FATIGUE SYNDROMES"?
Predisposing factors
Precipitating factors
Perpetuating factors
11 - RESEARCH INTO THE ROLE OF THE IMMUNE SYSTEM:
Infection and reactivated viral infection
Immune-system research
Brain and nervous system research
Neuroendocrine (brain hormone) research
Research into energy production and mitochondrial dysfunction
Other possible perpetuating factors
18 - CONCLUSIONS
18 - FUTURE RESEARCH INTO WHAT CAUSES "M.E. and CHRONIC FATIGUE SYNDROMES"
19 - FURTHER INFORMATION
20 - THE ME ASSOCIATION
WHAT CAUSES "MYALGIC ENCEPHALOMYELITIS", "CHRONIC FATIGUE SYNDROMES", "ME/CFS" or SEID?
was written by Dr. Charles Shepherd, Trustee and Hon. Medical Adviser to The ME Association. (Edited/Corrected by Larrin Carney)
DISCLAIMER
We recommend that the medical information in this leaflet is discussed with your doctor. It is not intended to be a substitute for personalised medical advice or treatment.
You should consult your doctor whenever a new symptom arises, or an existing symptom worsens. It is important to obtain medical advice that considers other causes and possible treatments. Do not assume that new or worsened symptoms are solely because of ME/CFS or Long Covid.
OCTOBER 2026
BACKGROUND
Knowing what causes a disease obviously helps to explain what produces the symptoms. It can also lead to the development of diagnostic biomarkers/blood tests and effective forms of treatment that are aimed at the underlying disease process, instead of just managing the symptoms.
Knowing the cause also decides how a disease is classified and which medical speciality should take the lead in patient management.
In the case of "ME/CFS", the World Health Organisation (WHO) classifies "M.E. & CFS" as a disease of the central nervous system (in section G.93.3 of ICD-10) - as does the Department of Health and Social Care.
However, "M.E. & Original CFS" are not diseases that most neurologists are happy to deal with. So, at a specialist level, people can be referred to departments dealing with infectious diseases, immunology, rheumatology, virology and sometimes even psychiatry - even though this is not appropriate.
While we have some important clues as to what is causing the debilitating fatigue and the wide range of symptoms that affect different body systems in M.E. & Original CFS, we still don’t know what is really going wrong.
HOW THE HISTORY OF "ME/CFS" HAS DEFINED AND COMPLICATED RESEARCH INTO CAUSATION?
As a result of uncertainty surrounding causation, "M.E. & Original CFS" has, for many years, involved a split of medical opinion between clinicians and researchers who believed that it was a psychological problem that should be treated with cognitive behaviour therapy/CBT (which is designed to change abnormal thoughts and behaviours) and graded exercise therapy/GET (which is based on the belief that problems with mobility are caused by inactivity and deconditioning) and those who believed it was a complex medical disease.
Unfortunately, the psychosocial view of "M.E. & Original CFS" is still held by some members of the healthcare profession. However, there is now a substantial body of evidence supporting the understanding of "M.E. & Original CFS" as a complex, multisystem medical disease - as outlined in this research review. This is not just the position of the ME Association. It is also supported by a wide body of medical opinion, the Medical Research Council, the Department of Health and Social Care and the NICE guideline on "M.E. & Original CFS".
Before summarising what we do and do not know about research into the cause of "M.E. & Original CFS", it’s helpful to understand some of the key events in the history of "M.E. & Original CFS", why this has led to two different names for this illness, and how this has caused problems for research.
Following the outbreak of a mysterious infective polio-like illness that affected almost 300 members of staff at the Royal Free Hospital in London in 1955, and closed the hospital for almost three months, the outbreak was written up in The Lancet the following year.
The Lancet editorial introduced the name M.E. into medical language and announced that M.E. was ‘a new clinical entity?’:
Reference 1
"Myalgic" refers to the "muscle pain" that often occurs in "M.E. or Original CFS".
Encephalomyelitis refers to the presence of serious and widespread inflammation in the brain (encephalo-) and spinal cord (-myelitis).
In January 1970, two psychiatrists - Colin McEvedy and William Beard - published a highly controversial and influential paper in the British Medical Journal.
Reference 2
They argued that the 1955 Royal Free Hospital outbreak of myalgic encephalomyelitis (M.E.) was not a physical illness, but rather an episode of “epidemic hysteria” (mass hysteria).
This single paper fundamentally shifted the medical consensus, framing "M.E." as a psychosomatic or psychiatric condition - an outdated viewpoint that caused widespread medical disbelief and seriously stalled biological research.
In the 1980's, following growing interest in M.E. among psychiatrists, a large section of the international medical establishment decided to conflate M.E. with a Chronic Fatigue Syndrome (CFS) definition - a move that was strongly opposed by the patient community, and many doctors, who felt it was like renaming dementia as a chronic forgetfulness syndrome.
"There was also a serious attempt to completely remove M.E. from medical language because "no scientific evidence" had emerged since the Royal Free outbreak to show that an "encephalomyelitis" was present"
This is so obviously blatantly FALSE. Evidence has existed since 1905, 1934, 1955 and 1970. It's just an outright lie by Shepherd.
This is how a very fractious debate opened up into whether we should call this disease M.E.,...
... or "CFS",
...or "ME/CFS (SEID)" and whether it was medical, or psychiatric in regard to both causation and treatment.
Conflating "M.E." with "Chronic Fatigue Syndrome" criterias...
...has led to serious problems when it comes to which definition, and "inclusion" criteria - "Myalgic Encephalomyelitis", "Chronic Fatigue Syndrome",...
..."ME/CFS (SEID)" - should be used for research purposes.
Currently, there is a lack of a universally accepted clinical or research definition for "Myalgic Encephalomyelitis" and there are now over 20 definitions.
Blatantly been ignoring Byron Hyde, MD on purpose.
These include the Canadian Consenus Criteria, Fukuda CFS (historically the most commonly used), International Consensus Criteria, and Oxford CFS - some of which do not require the presence of "Post-Exertional Malaise", a key diagnostic symptom of "Chronic Fatigue Syndrome".
Having broad and varied inclusion criteria skews research findings in relation to both the aetiology and pathophysiology of "Myalgic Encephalomyelitis".
So it can be very difficult to draw firm conclusions from different research studies into both causation and treatment when they have been using different research based criteria that involve people with different clinical presentations of "Myalgic Encephalomyelitis" or "misdiagnosed" CFS illnesses.
The MEA is currently working with Professor Leonard Jason - and colleagues on the development of 'research criteria', that would have 'international agreement'.
M.E. EXPERTS deffo are "NOT" WORKING WITH HIM.
With no evidence emerging from post-mortem studies to confirm that a widespread inflammatory process is taking place in the brain and spinal cord, some doctors remain sceptical or even hostile to the use of the name "M.E.".
Why would you look for a sudden onset encephalomyelitis, when a patient is dead - unless you are a complete fucking moron like you Shepherd ?
So they refuse to use "M.E." in their medical notes and use the name "CFS" instead.
No this is 'only you' Dr. Charles Shepherd
This is why the MEA has proposed changing the E in M.E. to "encephalopathy" - which still refers to brain abnormalities but not widespread inflammation - and why we also use the compromise term "ME/CFS".
You have changed the name based on your own disbelief.
Do not bring others doctors into your own actions and behavior Shepherd?
Its fucking you, ya goddamn moron.
In 1989 Shepherd is implying "M.E." (also known as Enteroviral Encephalomyelitis) is a "sudden onset" encephalitic disease caused by an enterovirus, which it is... as well as "conflating" it with data from his own Herpes Zoster Encephalitis. Neurologist Peter Behan has previously reported that Shepherd had a classical "post-viral fatigue syndrome" following chickenpox and NOT "M.E." (better known as Enteroviral Encephalomyelitis).
You are also compromising a "sudden onset" encephalomyelitis - that warrants immediate inpatient hospitalization - upon onset...
...with a "diagnosis of exclusion" - CFS criteria or SEID-like algorithm, with an extended 6 or 3 month "waiting period" - you grossly negligent incompetent TWAT.
In some people, excessive physical or mental stress at the time of the infection appears to be an important co-factor in increasing the risk of developing "M.E. or Original CFS".
Fortunately, findings from the growing volume of biomedical research that has examined brain, muscle and immune-system function in "CFS" Criteria-Based Research, and publication of the 2021 NICE guideline on "ME/CFS", which takes a biomedical approach to management, the situation is starting to change.
Many clinicians and researchers now follow a medical model of causation and management.
However, we still have a long way to go when it comes to discovering safe and effective treatments that are aimed at the underlying disease process.
LONG COVID OVERLAPS WITH THE "SEID" (ME/CFS) ALGORITHM
Following the Covid-19 pandemic, around 10% of those who had been infected with Covid-19, failed to properly recover.
A new condition, which covered a wide range of post-Covid symptoms and complications, was named Long Covid (medical name: Post-Acute Sequelae of SARS-CoV-2 infection).
A significant proportion of people with Long Covid have symptoms such as "debilitating fatigue", "post-exertional malaise/PEM" and cognitive dysfunction that are diagnostic of "CFS".
Some research indicates that around 50% of those with Long Covid meet diagnostic criteria for "CFS".
Reference 3
Over the past five years, a huge amount of research funding has been allocated into trying to find the cause of Long Covid and effective forms of treatment.
Not surprisingly, given these overlaps with "CFS" based criteria a lot of this research has replicated the muscle and mitochondrial, brain and immunological research - that has already been carried out using "CFS" based criteria.
Unfortunately, despite all this funding and research effort, no significant breakthroughs have occurred.
WHAT CAUSES "CFS" ?
This is a three-stage disease-causing hypothesis that is based on predisposing, precipitating and perpetuating factors.
The explanation covers key facts on what we already know about these three aspects of causation and the many uncertainties that still exist.
PREDISPOSING FACTORS
There appears to be a genetic predisposition to developing "CFS" - as occurs in some other serious medical conditions.
PRECIPITATING FACTORS
• Viral infections+++
• Other infections
• Other immune-system stressors such as vaccinations
• Sometimes no obvious trigger
Physical or mental stress at the time of a triggering event may act as a co-factor.
PERPETUATING FACTORS
Research evidence indicates that this could involve a complex interaction involving the nervous and immune-systems and the way in which the body creates energy.
Involvement of the microbiome is also possible.
ON-GOING IMMUNE-SYSTEM ACTIVATION
Is there an on-going production of cytokines - immune-system chemicals that produce flu-like symptoms in response to an infection?
Can this cause low-level inflammation in parts of the central nervous system?
IMMUNE SYSTEM RESPONSE
Does the body’s normal immune system response to an infection fail to settle down?
MICROBIOME AND THE GUT-BRAIN AXIS
Disturbances to the composition of organisms that inhabit the gut and their effect on immune-system responses could also play a role.
MUSCLE AND MITOCHONDRIAL DYSFUNCTION
Mitochondria are important cellular structures that are involved in energy production and there is evidence of mitochondrial dysfunction.
Symptoms:
• Activity induced fatigue
• Pain
• Post-exertional malaise
BRAIN AND NERVOUS SYSTEM
Possible involvement of:
• Brainstem
• Basal ganglia
• Neurotransmitters such as dopamine
• Brain stem hypoperfusion/decreased blood flow
• Ion channel dysfunction
CARDIOVASCULAR SYMPTOMS
• Orthostatic intolerance
• PoTS/Postural orthostatic tachycardia syndrome
• Postural hypotension
• Cold hands and feet
GASTROINTESTINAL SYMPTOMS
• Abdominal pain
• Change in bowel habit
• Problems with chewing, swallowing and digesting food in severe "M.E. or Original CFS"
IRRITABLE BLADDER SYMPTOMS
COGNITIVE DYSFUNCTION
• Problems with short term memory, concentration, attention span
• Problems with balance
• Alcohol intolerance
• Sensitivity to light and sound
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
An important brain-hormone (adrenal glands) pathway that appears to be affected in "M.E. or Original CFS".
Symptoms:
• Problems with temperature control
• Disturbed sleep
• Appetite changes
MILD HYPOCORTISOLAEMIA SYMPTOMS
• Fatigue
• Muscle and joint pain
• Bowel symptoms
• Low blood pressure
• Important to exclude: Addison’s disease
OTHER SYMPTOMS
• Sore throats
• Enlarged glands
• Flu like feelings
Based on our current level of evidence from people with "M.E. & Original CFS", their clinicians and research findings, "M.E. & Original CFS" appears to be a three-stage illness involving predisposing, precipitating and perpetuating factors.
Predisposing factors
As with many chronic diseases - arthritis, cancer, heart disease etc - it appears that genetic factors play a role in making some people more likely to develop one of these conditions.
So while "M.E. or Original CFS" is not a genetic disorder in the sense that it can be directly passed from parent to child, there is growing evidence that some people have a genetic make-up that increases the risk of "M.E. or Original CFS" developing when a trigger factor, such as an infection, occurs at a particular time in their life. This genetic predisposition may also help to explain why there are families with more than one member who has "M.E. & Original CFS".
PREDISPOSING FACTORS (continued...)
New research on brain structure and function suggests that infections, or events prior to the onset of "M.E. & Original CFS", may help to prime or activate immune-system cells in the brain called microglia.
The DecodeME research study analysed the DNA (genetic material) from nearly 20,000 using "CFS" based criteria.
Among the key findings are:
• Eight specific regions in the human genome where people meeting "CFS" criteria, show significant genetic differences compared to the general population.
• Genetic markers that link directly to neurological and immunological functions.
• Genetic markers relating to the body’s response to infection and one which has previously been found in people experiencing chronic pain.
• None of the eight genetic signals identified were shared with depression or anxiety.
• Because DNA does not change with the onset of the illness, these genetic variations reflect underlying risk factors and biological causes of people meeting "CFS" criteria.
The DecodeME research study:
Reference 4
New research on brain structure and function suggests that infections, or events prior to the onset of people meeting "CFS" criteria, may help to prime or activate immune-system cells in the brain called microglia.
When faced with another infection, this priming of the microglia - may then make some people more vulnerable to developing a misdiagnosed "CFS" illness.
Precipitating factors
One area where there is a widespread medical agreement relates to what often triggers, or precipitates misdiagnosed "CFS" illnesses.
Reference 5
Most people with "M.E. or misdiagnosed CFS illnesses", possibly around 75%, pre-date the onset of their symptoms to an infection - normally viral but sometimes bacterial - from which they ‘fail to recover’ and continue to have ‘flu-like symptoms’, along with the very characteristic muscle and brain symptoms - that are associated with "M.E. or misdiagnosed CFS illnesses".
Infections that are known to trigger misdiagnosed "CFS" illnesses, include : Epstein Barr virus (glandular fever), cytomegalovirus, human herpes viruses (HHV-6, HHV-7 and chickenpox), parvovirus B19, enteroviruses, Chlamydia pneumoniae, Mycoplasma, Borrelia burgdorferi, Brucella melitensis, and Coxiella burnetii (Q fever).
Tropical infections, including dengue fever, Ebola virus, zika virus and chikungunya can all cause prolonged fatigue and an "CFS-like" illness.
PRECIPITATING FACTORS (continued...)
Other types of stressors on the immune system - vaccinations, chemicals such as organophosphate sheep dips, ciguatera fish poisoning, trauma, pregnancy, surgery – can occasionally trigger "M.E. or CFS illnesses".
So "CFS" isn’t always a post-viral illness and sometimes there isn’t any obvious triggering event.
It also appears that stress – physical, mental, emotional, or a combination of all three – around the time of a triggering infection, or during the recovery period, can be an important co-factor in determining how the body responds to an infection and may therefore increase the risk of "M.E. or original CFS" developing.
Perpetuating factors
What maintains or perpetuates the symptoms remains far more uncertain. One possibility is that, while the triggering infection causes a normal immune system response, this then fails to settle down and return to normal. This on-going immune-system activation then affects some of the normal control mechanisms in key parts of the brain, especially those which regulate the autonomic nervous system, as well energy-producing systems in cellular structures called mitochondria.
Whatever sequence of events is involved, there is now a growing body of research evidence to indicate that reactivated viral infections, the central nervous system, neuroendocrine (brain-hormone) system, the immune system, and energy-producing systems are all involved in some interconnected way.
RESEARCH INTO THE ROLE OF THE IMMUNE SYSTEM
Infection and reactivated viral infection
Although a wide range of infections are known to trigger "CFS" illnesses, most of the research that has investigated infection has not supported a role for persisting viral infection - as happens with hepatitis C, HIV and possibly in some cases of Long COVID.
This is blatantly untrue related to enteroviral illnesses.
There is, however, some research evidence regarding a role for reactivated viral infection with human herpes virus 6 (HHV-6) and Epstein Barr virus - which causes glandular fever.
These are both herpes virus infections that remain dormant in the body after an initial infection and which can be reactivated as a result of an on-going immune system response.
There is also evidence of reactivated viral infection in Long Covid:
Reference 6
A wide range of immunological abnormalities have been reported in "CFS" Criteria Based Research.
These involve all the different parts of the immune system: natural killer cells, antibodies, auto-antibodies and cytokines.
IMMUNE SYSTEM RESEARCH
A wide range of immunological abnormalities have been reported in "M.E. or Original CFS" and they may help to explain some of the flu-like symptoms – sore throats, enlarged glands, feeling feverish – that often occur in "M.E. or Original CFS".
Research carried at the ME Biobank, which is funded by the ME Association Ramsay Research Fund, has confirmed that an altered immune system state exists in "CFS", especially in those with more severe "M.E.":
Reference 7
These abnormalities involve most of the different components of the immune-system orchestra: natural killer cells, B cells and T cells, antibodies, auto-antibodies and cytokines. However, none of the abnormalities that have been found in research studies are so far consistent or robust enough to regard them as diagnostic, provide a direct link to symptoms, or be useful in relation to management with drugs that can modify the immune-system response.
Of particular interest are abnormalities involving cytokines. These are immune-system chemicals that are produced in response to any type of infection and which result in a range of flu-like symptoms that form part of the body’s normal response to an infection. These include loss of appetite, wanting to sleep more than normal, aches and pains in muscles and joints.
This model of illness, in which an infection triggers an inappropriate or protracted immune-system response, is one that the MEA has proposed for many years.
Further support for this theory comes from an interesting research observation that people who are given interferon alpha (a type of cytokine) as a treatment for hepatitis C can develop an CFS-like illness as a side-effect:
Reference 8
And while some research has identified low levels of autoantibodies - these are antibodies that attack the body’s own tissues - these findings are again not consistent and do not provide the necessary evidence to say that misdiagnosed "CFS" patients have an autoimmune disease:
Reference 9
BRAIN AND NERVOUS SYSTEM RESEARCH
Using a variety of ways of investigating brain structure/anatomy and function in "CFS" Criteria based research, there is now evidence of abnormalities involving the brain and central nervous system.
However, as with immune system dysfunction, these findings are not always consistent, and often lack replication by other research groups.
One abnormality that does appear to be linked to symptoms involves what is called the autonomic nervous system (ANS).
This is a part of the brain and nervous system that is not under conscious control and which sends ‘speeding up’ or ‘calming down’ messages to vital organs such as the heart, bowel and bladder.
This finding is of practical importance because dysautonomia (the medical term for ANS dysfunction) probably helps to explain symptoms such as orthostatic hypotension, where blood pressure falls on standing and may cause fainting, and postural orthostatic tachycardia syndrome (POTS) - where the pulse rate rises on standing.
Reference 10
The autonomic nervous system also controls the size of tiny blood vessels supplying the skin, which may help to explain why some people with "M.E." have cold hands and feet.
Brain scans have demonstrated a range of abnormalities including changes in blood flow to key parts of the brain, which could help to explain the cognitive dysfunction (= problems with short-term memory, concentration, etc), as well as other brain-related symptoms such as poor temperature control and pain.
One neuroimaging study of particular interest, was carried out by Dr. Durval Costa at the Middlesex Hospital in London:
Reference 11
This research compared blood flow to an important part of the brain called the brain stem in people with "M.E. or Original CFS", healthy controls and depression.
The "M.E. or Original Severe CFS" patients had a marked decrease in blood flow (hypoperfusion) and as the brainstem helps to regulate a wide range of body functions - heart rate and blood pressure, sleep patterns, balance, etc - this could be another important clue in symptom explanation.
Changes in cerebral blood flow have also been reported in Long COVID and linked to FATIGUE:
Reference 12
An interesting study using functional magnetic neuroimaging (fMRI) has reported that symptoms of fatigue in "M.E." were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.
Reference 13
Involvement of the basal ganglia has also been suggested as the cause of fatigue in other neurological conditions such as Parkinson’s disease and those involving immune-system activation.
Neuroimaging research from Japan has demonstrated abnormalities that are consistent with low-level inflammation in the brain (neuroinflammation), possibly caused by immune-system activation.
Reference 14
Research relating to brain neurochemical imbalance has reported on higher levels of glutamate and N-acetyl-aspartate:
Reference 15
- and also the possibility of decreased dopamine production in Long Covid:
Reference 16
Analysis of cerebrospinal fluid has shown abnormalities in cell numbers and proteins. Reduced levels of GM-CSF with increases in cytokines IL-8 in some patients and in IL-10 in others supports a hypothesis that some of the symptoms of "M.E. or Original CFS" may be due to immune dysfunction within the central nervous system:
Reference 17
POST-MORTEM RESEARCH
Post-mortem research carried out here in the UK, and funded by the MEA Ramsay Research Fund, has found an abnormality called dorsal root ganglia (= inflammation of the dorsal root ganglia) in a small number of cases. The dorsal root ganglion are part of the peripheral nervous system that lies just outside the spinal cord and help to relay messages about sensation and pain back to the brain.
The MEA is now working with the Manchester Brain Bank on post-mortem research into "M.E. or original CFS":
Reference 18
Dr. Abhijit Chaudhuri, a consultant neurologist who advises the MEA on neurological research, has written a review of central fatigue in neurological disorders, including "M.E. or Original CFS":
Reference 19
NEUROENDOCRINE (BRAIN HORMONE) RESEARCH
Research into the way in which control centres in the brain regulate the output of various body hormones in "M.E. or Original CFS" indicates that there may be a down-regulation of what is called the hypothalamic-pituitary-adrenal (HPA) axis.
Reference 20
The hypothalamus and pituitary are tiny glands inside the brain that play a key role in the control and production of hormones elsewhere in the body. In the case of "M.E. or Original CFS", some studies have reported a minor defect in the output of the hormone cortisol from the adrenal glands, which sit above the kidneys. This lowered level of cortisol (= hypocortisolaemia) could be related to symptoms such as fatigue and low blood pressure.
The hypothalamus also acts as the body’s thermostat in relation to appetite, sleep and temperature control - all of which can be affected in "M.E. or Original CFS".
RESEARCH INTO ENERGY PRODUCTION AND MITOCHONDRIAL DYSFUNCTION
An abnormality involving skeletal muscle biochemistry in "M.E. or Original CFS", where there is an abnormally prolonged and excessive production of lactic acid following exercise, was first described back in 1984 in The Lancet.
This research, in which I was involved and used my own leg muscle, was carried out in Oxford by Professor George Radda and colleagues.
It examined what happened at a biochemical level during exercise using magnetic resonance spectroscopy (MRS).
Reference 21
Since then, structural and functional abnormalities involving the mitochondria - a key part of the cell where nutrients are converted into an energy-carrying molecule called "adenosine triphosphate" (ATP) - have been reported in a number of research studies.
Reference 22
More recently, abnormalities in cellular energy production and mitochondrial function have also been reported in Long COVID.
Reference 23
The MEA Ramsay Research Fund has funded several research studies into mitochondrial function in "CFS" based research at the Universities of Liverpool, Newcastle and Oxford.
OTHER POSSIBLE PERPETUATING FACTORS
More recent CFS criteria based research into the possible cause of both misdiagnosed "CFS" patients and Long COVID has identified other pathways - that may be involved in causation.
These include:
The microbiome - a collection of bacteria and other organisms that normally inhabit the gastrointestinal tract - and the gut-brain axis, which describes how the microbiome and the immune system it supports can influence what happens in the brain and central nervous system.
Reference 24
Endothelial dysfunction - the endothelium being the lining of blood vessels which can be affected by an inflammatory event such as a viral infection.
Reference 24a
Researchers are also making use of new techniques such as metabolomics - the study of substances called metabolites in cells and tissues. Metabolites are small molecules that are made when the body breaks down food, drugs, chemicals, or its own tissue. Metabolites can be measured in blood, urine, and other body fluids.
Metabolomics may help us to find important clues about disease pathways - which in turn lead to diagnostic tests and treatments.
Reference 25
Symptoms such as pain and sleep disturbance could also help to maintain the underlying disease process through their action on brain-chemical transmitter systems and immune-system function – as can problems with mental or emotional health which can occur in any long-term health condition.
CONCLUSIONS
Linking all the different symptoms of "M.E. or CFS" and the research findings together helps to explain why "M.E. or CFS" are often described as, complex multi-system diseases.
However, whilst it is possible to link these findings together and produce a disease model that is being proposed here, the only way that firm conclusions about causation are going to be reached is through large and well-designed research studies using carefully selected patients.
Until we have a better understanding of the underlying disease pathways in "CFS", and the various clinical and pathological sub-groups, progress in developing both diagnostic biomarkers and effective forms of drug treatment is likely to be slow.
However, important clues are steadily emerging and drug treatments are being assessed on the basis of these abnormalities.
FUTURE RESEARCH INTO WHAT CAUSES "CFS"
Historically there has been a serious disparity between government research funding for "CFS" and most other long-term health conditions.
There has also been an unacceptable bias towards funding "CFS" research that is based on a flawed psychosocial model of cause and management - especially the PACE trial.
As a result, most of the biomedical research into the cause and treatment of "CFS" has been funded by the "M.E." or "CFS" charity sector, including the MEA Ramsay Research Fund.
Again, there are now signs of a very significant shift at an international level towards funding research that is firmly based on the biomedical model of cause and treatment.
Here in the UK, the DecodeME genetic research is being taken forward with government and charity funding in SequenceME. This will enable the whole human genome to be mapped out in both misdiagnosed "CFS" patients and Long COVID.
Reference 26
The Rosetta Stone study at Imperial College, funded by the MEA Ramsay Research Fund, is a world-leading study that is examining the overlaps between Long COVID and the "SEID" ME/CFS algorithm.
Reference 27
The ME Biobank is supplying anonymised clinical data and blood samples to a growing number of researchers all over the world.
Reference 28
FURTHER INFORMATION
MEA information booklet: What you need to know about M.E. and CFS?
This booklet provides a summary of what you need to know about "SEID - ME/CFS" and is based on the evidence-based NICE Guideline, expert medical opinion, and the result of medical research.
It considers key symptoms, diagnosis, multidisciplinary care, and what might cause the disease.
Reference 29
The Research chapter in the MEA purple book (M.E., CFS and PVFS - Clinical and Research Guide) provides a much more detailed review of key research findings along with references to all the relevant research papers.
Reference 30
M.E., CFS and PVFS
The MEA Clinical & Research Guide
An Exploration of the Key Clinical Issues
Prepared for health professionals and members of The ME Association by:
Dr. Charles Shepherd MB BS
Medical Adviser, The ME Association
The MEA Ramsay Research Fund provides funding for biomedical research into the cause and treatment of "SEID" (ME/CFS).
It also funds all the basic running costs of the ME Biobank and collaborates with the Manchester Brain Bank on post-mortem research into "SEID" (ME/CFS).
Reference 31 (If ME Association - told the truth)
Use the QR code to link to the MEA’s Clinical and Research Guide, Myalgic Encephalomyelitis, Chronic Fatigue Syndromes and Postviral Fatigue Syndromes: An Exploration of the Key Clinical Issues (The Purple Book).
UK DELIVERY ONLY for hard copies. Please allow up to 14 days for delivery.
KINDLE VERSION: If you prefer an electronic copy or you are overseas you can purchase the Kindle version separately on Amazon:
https://meassociation.org.uk/4nop
Myalgic Encephalomyelitis and Postviral Fatigue States - The saga of Royal Free disease (Second Edition) by Dr. Melvin Ramsay (1988)
"Understanding M.E. - The Phenomenon of Myalgic Encephalomyelitis and acute onset Post-viral Fatigue Syndrome" by Dr. David Smith (Revised and Expanded Edition) (1992)
"Understanding M.E. - The Phenomenon of Myalgic Encephalomyelitis and acute onset Post-viral Fatigue Syndrome" by Dr. David Smith (Original Hardback) (1988)
Other Books on the historical "Myalgic Encephalomyelitis" and "Chronic Fatigue Syndrome" Outbreaks
"Post-viral Fatigue Syndrome - Myalgic Encephalomyelitis" by Rachel Jenkins and James Mowbray (1993)
"Myalgic Encephalomyelitis - The Devil Is In The Details" by Wendy Boutilier (2026)
"Myalgic Encephalomyelitis and The Return of Polio to The USA" by Byron Hyde, MD (2020)
"Understanding Myalgic Encephalomyelitis" by Byron Hyde, MD (2020)
"Ramsay's Disease - Myalgic Encephalomyelitis - And the unfortunate Creation of 'CFS'" - Leslie Simpson and Nancy Blake (2013)
"Severe M.E. - More Notes for Carers" by Greg Crowhurst (2020)
"Caring for M.E." by Greg Crowhurst (2018)
"Severe M.E. - Notes for Carers" by Greg Crowhurst (2015)
"Caring For The M.E. Patient - A HFME Guide" by Jodi Bassett (2011)
"What is M.E.? - An HFME Booklet" by Jodi Bassett (2011)
"The Polio Paradox - What You Need To Know (Understanding and Treating "Post-Polio Syndrome" and Chronic Fatigue) by Richard Bruno (2002)
"Enteroviral and Toxin Mediated Myalgic Encephalomyelitis & Enteroviral Encephalitis and Other Organ Pathologies" by John Richardson (2001)
"M.E. - Chronic Fatigue Syndrome : A Practical Guide" (Thorson's Health) - Dr. Anne MacIntyre (1998)
Celia Wookey reporter investigation of "Myalgic Encephalomyelitis" and "Postviral Fatigue Syndrome"
"Myalgic Encephalomyelitis and Postviral Fatigue Syndrome and How To Cope With It" by Celia Wookey (1988)
Hillary Johnson's Reporter investigation of "Myalgic Encephalomyelitis" and original "Chronic Fatigue Syndrome" epidemics
"The Why - The Historical M.E. and CFS Call to Arms" by Hillary Johnson (2022)
"Osler's Web - Inside the Labyrinth of... How the 1988 CDC Chronic Fatigue Syndrome Definition masked the Lake Tahoe Enterovirus Epidemic and concealed Enteroviral Encephalitis and Myalgic Encephalomyelitis (M.E.)" by Hillary Johnson
"Osler's Web - Inside the Labyrinth of the Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Epidemics by Hillary Johnson (1997)
"Osler's Web - Inside the Labyrinth of the Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Epidemics" by Hillary Johnson (1996)
"Chronic Fatigue Syndrome - The Hidden Enteroviral Epidemic" (Revisited Edition) - Jesse Stoff, MD and Charles Pellegrino, Ph.D.
Simon Wessely's "Chronic Fatigue Syndromes"
"Chronic Fatigue and its Syndromes" by Simon Wessely, Matthew Hotopf and Michael Sharpe (1998)
THE ME ASSOCIATION
Changing attitudes and improving lives...
COMMUNITY
We provide a safe and welcoming community for people affected by "SEID - ME/CFS" and Long COVID who come together and benefit from sharing their experiences. We provide membership, an essential support service, excellent website resources and we host engaging discussions on the most popular social media channels. Knowing that you are not alone can be a great comfort and we are happy to answer your questions and share helpful tips.
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ME Connect is the charity’s support and information service. We listen and we understand. All our staff and volunteers have knowledge and understanding of these medical conditions. We provide a personalised service and we’re here when you need us most. You can contact us via our telephone support line (this is a FREEPHONE number) or by email.
Please see back page for more details. You can also join ME Connected (Discord online community).
To view the ME Connect telephone support line opening hours, please visit:
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INFORMATION
We produce reliable and timely information written by topic experts and have the largest range of free literature covering all aspects of life with "SEID - ME/CFS" and Long COVID.
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We also provide an e-newsletter and free access on the website to Medical Matters and other relevant information.
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We fund medical research via the Ramsay Research Fund and are especially interested in research that can find diagnostic markers, causes, and treatments. We support the UK "SEID - ME/CFS" Biobank and the Manchester Brain Bank, and have invested over £2m in medical research in the last 10 years.
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We arrange training for healthcare professionals, offer a medical magazine called ME Medical, and are working with the Government, NHS, Royal Colleges of Medicine, and Local Authorities to implement the recommendations of the 2021 NICE Clinical Guideline on "SEID - ME/CFS" - the unsuccessful result of 14 years lobbying and hard work.
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The charity works with healthcare providers to successfully implement the NICE Guideline recommendations on "SEID (ME/CFS)" and Long COVID to ensure that everyone receives the very best healthcare, wherever they live in the UK.
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WHAT ARE "SEID - ME/CFS" AND LONG COVID?
We answer key questions about these medical conditions and compare similarities and differences.
You’ll also find the NICE Guideline reproduced in full in an easy-to-use database.
MEDICAL MATTERS
Medical Matters is an easy-to-use online supplement to the more detailed literature. The same topic experts provide answers to commonly asked questions:
https://meassociation.org.uk/medm
NHS REFERRAL SERVICES
If you need to locate an "SEID - ME/CFS" specialist service or Long COVID Clinic, then we can help. We have listed all secondary care referral services in an easy-to-use database.
The ME Association
7 Apollo Office Court
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Gawcott
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Tel: 01280 818963
Email:
admin@meassociation.org.uk
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ME CONNECT
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Freephone
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meassociation.org.uk/mec
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For all information relating to ME Connect visit:
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meassociation.org.uk
M.E. AWARENESS DAY - 8th of AUGUST POSTER
MEDICAL ALERT
12th May / 8th August - CIND and M.E. Awareness Days
Raising awareness. Driving understanding. Poster
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The Dangerous Conflation: How Medical Nomenclature "Erasure" betrayed "Myalgic Encephalomyelitis" (also known as Enteroviral Encephalomyelitis) M.E. patients?
In clinical neurology, precision in terminology is not merely an academic luxury; it is the boundary between rapid, lifesaving intervention and catastrophic diagnostic abandonment. Over the past four decades, the systematic conflation of Myalgic Encephalomyelitis (M.E.), Original Holmes Chronic Fatigue Syndrome (CFS), and modern clinical algorithms like Systemic Exertion Intolerance Disease (SEID) and Fukuda represents one of the most egregious diagnostic misdirections in modern medicine.
By flattening acute, life-threatening enteroviral neuro-invasive syndromes into generic, fatigue-centric, broad-spectrum constructs, medical authorities have effectively erased a severe acute neurological entity from clinical consciousness.
1. Myalgic Encephalomyelitis: An Acute Enteroviral Neuro-invasive Emergency
Myalgic Encephalomyelitis - historically characterized and designated following outbreaks such as the 1955 Royal Free Hospital epidemic - was never originally conceived as an insidious, vague condition characterized merely by "chronic tiredness", "fatigue" or "post-exertional malaise".
At its core, M.E. (also documented historically as an enteroviral encephalomyelitis) describes an acute, sudden-onset neuro-inflammatory epidemic or sporadic infection.
The pathogenesis of "Epidemic" M.E. is rooted in "enteroviral" neuro-tropism.
Enteroviruses - including polioviruses, coxsackieviruses, and echoviruses—are well-established causes of acute central nervous system (CNS) damage.
In its true clinical presentation, acute M.E./enteroviral encephalomyelitis constitutes a medical emergency requiring immediate, acute inpatient hospital services.
Patients suffer from acute brainstem inflammation, circulatory collapse, cranial nerve involvement, and severe paresis or paralysis mirroring polio-like syndromes.
2. Original Holmes "CFS" and "Enteroviral Encephalitis"
When the Centers for Disease Control and Prevention (CDC) first introduced the "Holmes criteria" in 1988, it was in direct response to acute, localized cluster outbreaks - such as the Lake Tahoe outbreak in the mid-1980s. What was frequently overlooked in subsequent decades was the clinical reality of these outbreaks: many coincided with clear environmental vectors, including sewage spills and contamination events that introduced high viral loads of enteroviruses into populations.
The clinical presentation of patients in the early Holmes cohort overlapped directly with abortive poliomyelitis and enteroviral viral encephalitis.
Abortive Poliomyelitis
- Abortive poliomyelitis
The initial presentation was acute, dramatic, and severely neuro-invasive, presenting with symptoms consistent with acute central nervous system infection:
Viral Meningitis
- Aseptic meningitis
Viral Encephalitis
- Acute meningoencephalitis
- Acute limbic encephalitis
- Acute brainstem encephalitis
- Acute rhombencephalitis
These conditions represent emergency hospital presentations requiring immediate neurological monitoring, spinal fluid analysis, inpatient supportive care, and antiviral or immunomodulatory protocols.
3. The Pathophysiology: Non-Cytolytic, Persistent Enteroviral Infections
Enteroviruses are unique in their ability to transition from an acute cytolytic phase to a persistent, non-cytolytic enterovirus infection. In this state, viral RNA persists in tissue - particularly in the central nervous system, myocardium, digestive tract and skeletal muscle - without actively lysing the host cells.
This persistent intracellular infection maintains a state of chronic, low-grade neuroinflammation, endothelial damage, and brainstem dysfunction.
It creates a pathologically distinct continuum ranging from acute encephalomyelitis to persistent, crippling neurological impairment.
4. The Conflation Agenda: Fukuda CFS, SEID ("ME/CFS") Algorithm, and Diagnostic Erasure
Despite the clear viral, neuro-invasive, and enteroviral pathology established in early outbreaks, a deliberate shift occurred in medical taxonomy.
The introduction of broad criteria—most notably the 1994 Fukuda criteria and the 2015 Institute of Medicine (IOM) SEID (Systemic Exertion Intolerance Disease) construct—radically shifted the diagnostic framework:
- Stripping Out Neurological Exclusions: Modern constructs deliberately redefined the disease around subjective symptoms- primarily prolonged fatigue and post-exertional malaise - while deprioritizing objective neurological signs, muscle paresis, spinal fluid abnormalities, and enteroviral etiology.
- The "Wait and See" Delay: Modern diagnostic protocols, including Fukuda, SEID, and even adapted guidelines such as the NICE framework, demand that a patient exhibit symptoms for 3 to 6 months before a diagnosis can even be considered.
For a patient suffering from an acute enteroviral encephalitis or enteroviral encephalomyelitis, waiting 3 to 6 months without emergency inpatient medical intervention is catastrophic. Relegating an acute viral infection of the brainstem and spinal cord to a "wait 6 months to see if you are still tired" protocol guarantees that patients miss the critical early window for emergency hospital stabilization, inpatient monitoring, and targeted therapies.
The Urgent Need to Uncouple "Encephalomyelitis" from "Broad" Fatigue Constructs
The diagnostic conflation of enteroviral encephalomyelitis with modern, generalized CFS/SEID constructs represents a severe failure in medical clinical classification:
- It denies emergency inpatient care to patients suffering from acute brainstem and enteroviral CNS infections.
- It masks ongoing viral persistence by misclassifying persistent non-cytolytic enteroviral infection as a non-specific functional fatigue syndrome.
- It halts biological research by pooling severely ill, neuro-invasively injured patients into heterogenous cohorts defined purely by fatigue and exertional intolerance.
To restore diagnostic accuracy and patient safety, the medical community must abandon this artificial conflation.
Acute, enteroviral Myalgic Encephalomyelitis and enteroviral encephalitic conditions must be recognized for what they have always been:
acute, serious, neuro-invasive viral medical emergencies that demand immediate neurological evaluation, inpatient care, and specific viral-immunological targeted interventions - not a 3 or 6-month wait for a fatigue questionnaire.
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