When Overlap Becomes Conflation

Enteroviral CNS Disease, Ramsay M.E., Chronic Fatigue Syndrome, SEID algorithm, ME/CFS and Long COVID must be distinguished

Introduction

The history of Myalgic Encephalomyelitis (M.E.), Chronic Fatigue Syndrome (CFS), ME/CFS and Systemic Exertion Intolerance Disease (SEID) has produced a succession of definitions with substantial symptom overlap.

Long COVID has now added another broad clinical category containing many of the same symptoms.

The overlap is real.

But overlap is not proof that the underlying diseases are identical.

This distinction becomes particularly important when symptoms belonging to an identifiable acute infectious neurological disease - such as enteroviral encephalitis, brainstem encephalitis, encephalomyelitis or poliomyelitis-like disease - are subsequently absorbed into a nonspecific fatigue or post-viral classification.

The original 1988 Holmes CFS definition itself illustrates the problem. Holmes CFS required new debilitating fatigue plus a large collection of symptoms including fever or chills, sore throat, painful lymph nodes, muscle weakness, myalgia, prolonged post-exercise fatigue, headache, joint pain, neuropsychological complaints including photophobia and confusion, sleep disturbance and an illness developing over hours or days. It additionally recognised objective low-grade fever, non-exudative pharyngitis and tender lymph nodes.

Those are not disease-specific symptoms.

Several can occur during acute infectious illnesses, including enteroviral illness.

The danger is therefore straightforward:

A PATIENT CAN MATCH A SYMPTOM DEFINITION WITHOUT THAT DEFINITION IDENTIFYING THE DISEASE CAUSING THE SYMPTOMS.

The Diagram Shows Criteria Overlap - Not Biological Equivalence

The overlapping-definition diagram is valuable because it demonstrates how radically the patient population can change according to the criteria selected.

Different boxes encompass different combinations of:

fatigue,
post-exertional malaise,
cognitive impairment,
sleep disturbance,
orthostatic intolerance,
myalgia,
headache,
sore throat,
tender lymph nodes,
joint pain,
flu-like symptoms,
mild fever,
muscle weakness,
photophobia,
temperature intolerance,
gastrointestinal and genitourinary abnormalities,
cardiovascular manifestations,
sensory hypersensitivity,
and motor disturbance.

Even a systematic review of the case definitions found substantial differences between them and noted that validation had been highly variable.

The diagram therefore should not be interpreted as:

“These are different names for the same disease.”

A more defensible interpretation is:

“These definitions select overlapping populations using different combinations of nonspecific and more specific clinical features.”

That distinction changes everything.

The Original Holmes CFS Definition and an Acute Infectious-Like Presentation

The original 1988 Holmes CFS definition deserves separate attention.

Holmes and colleagues explicitly proposed CFS as a new name for what had been called “chronic Epstein-Barr virus syndrome”. They described it as a syndrome of unknown cause characterised primarily by chronic fatigue and created the working definition to improve research comparability.

Yet the criteria contained a striking collection of acute infectious-like manifestations.

These included:

mild fever or chills;
sore throat;
painful cervical or axillary lymph nodes;
muscle weakness;
myalgia;
headache;
joint pain;
neuropsychological manifestations including photophobia and confusion;
and a symptom complex developing over a few hours or a few days.

The required physical findings could include:

documented low-grade fever;
non-exudative pharyngitis; and
palpable or tender lymph nodes.

These features have considerable phenomenological overlap with the nonspecific systemic phase of numerous viral infections.

They can also resemble features occurring in minor/abortive poliovirus infection, which historically can produce fever, sore throat, headache, gastrointestinal disturbance and myalgia without paralytic disease.

That is an overlap in clinical presentation, however - not evidence that Holmes CFS was poliomyelitis, or that everyone meeting Holmes criteria had an enterovirus.

That distinction must remain explicit.

Abortive Polio provides an important historical comparison

Poliovirus is itself an enterovirus.

Most poliovirus infections do not produce paralytic poliomyelitis.

The early or minor illness can involve nonspecific manifestations such as:

fever,
sore throat,
headache,
malaise,
nausea or vomiting,
and muscular discomfort.

Only a minority of infections progress to CNS involvement and an even smaller proportion to paralytic disease.

This illustrates an important general principle about enteroviruses:

THE SAME VIRAL FAMILY CAN PRODUCE VERY DIFFERENT CLINICAL SEVERITIES AND ANATOMICAL PATTERNS.

An enteroviral infection may remain a systemic illness.

Another may produce meningitis.

Another may involve the brain.

Another may involve the brainstem.

Another may involve the spinal cord or anterior horn cells.

Therefore, nonspecific “flu-like” onset symptoms alone cannot tell us where an enteroviral infection will ultimately localise.

Enteroviral Encephalitis is different from a Fatigue Classification

Once the CNS is involved, the clinical problem changes fundamentally.

Enteroviral encephalitis is an acute infectious neurological disease.

Depending upon the affected structures and severity, neurological manifestations may include:

headache,
photophobia,
altered cognition,
confusion,
altered consciousness,
seizures,
ataxia,
motor abnormalities,
cranial-nerve abnormalities,
autonomic dysfunction,
and other focal neurological signs.

These manifestations can superficially overlap with symptoms appearing within CFS, ME/CFS criterias or the SEID algorithm.

But the diagnostic meaning is completely different.

For example:

cognitive impairment in a symptom algorithm

is not equivalent to

cognitive impairment during encephalitis.

Likewise:

muscle weakness in a CFS questionnaire

is not equivalent to

acute flaccid weakness associated with neurological infection.

The symptom may have the same English name.

The pathology need not be the same.

Anatomical Localisation Matters: Limbic and Brainstem Disease

The word “encephalitis” is itself anatomically broad.

Different forms of encephalitis may preferentially involve different regions.

Limbic involvement

Disease involving limbic structures can produce prominent:

memory impairment;
behavioural or emotional change;
confusion;
seizures;
altered cognition; and
disturbances of autonomic or hypothalamic-associated functions depending upon the broader anatomical involvement.

A symptom list may record this merely as:

“cognitive impairment.”

But neurological medicine asks a more important question:

Which structures are dysfunctional and why?

Brainstem involvement

Brainstem encephalitis can produce an entirely different constellation:

cranial-nerve palsies;
abnormal eye movements;
diplopia;
facial weakness;
dysarthria;
dysphagia;
autonomic instability;
motor abnormalities; and
respiratory compromise.

Reducing those manifestations to “fatigue”, “brain fog”, “dizziness” or “neurological symptoms” destroys clinically important anatomical information.

Enteroviral Encephalomyelitis extends Beyond the Brain

Where both the brain and spinal cord are involved, the clinical picture can extend further.

Potential manifestations of an encephalomyelitic process can include:

brain/brainstem abnormalities

together with

limb weakness, motor dysfunction, sensory disturbance, altered reflexes, bladder/bowel dysfunction or other spinal manifestations.

Again, this is fundamentally different from identifying patients because they report a particular collection of chronic symptoms.

The appropriate questions become:

Is there CNS inflammation?

Which regions are affected?

Is the spinal cord involved?

Are anterior horn cells or peripheral motor pathways involved?

Is there an identifiable infectious cause?

Anorexia and Feeding difficulty should NOT Be Ignored

The diagram is also interesting because anorexia appears within the Ramsay-associated area.

Here terminology matters.

In neurological and infectious medicine, anorexia means loss of appetite. It does not necessarily mean the psychiatric disorder anorexia nervosa.

Loss of appetite and reduced intake can accompany acute viral infection.

More severe neurological disease can create additional feeding problems through entirely different mechanisms.

A child or infant with severe neurological infection may develop poor feeding because of systemic illness, altered consciousness, bulbar dysfunction or impaired swallowing.

An adult may develop:

loss of appetite,
weight loss,
nausea,
dysphagia,
impaired swallowing,
or inability to maintain adequate nutrition.

Therefore, “anorexia” should not simply be treated as an incidental fatigue symptom.

The clinical question is:

Why is the patient failing to eat?

Loss of appetite, gastrointestinal disease and neurological dysphagia are different mechanisms and need to be distinguished.

Ramsay M.E. should be Considered separately

Ramsay M.E. should then be considered on its own terms rather than retrospectively equated with every later CFS definition.

Ramsay's description emphasised a characteristic pattern including:

acute onset,
neurological disturbance,
muscle fatigability,
delayed restoration of muscle power,
marked fluctuation,
and a prolonged or relapsing course.

That is not simply the same thing as asking whether somebody has had unexplained fatigue for six months.

This distinction is precisely why the diagram places Ramsay separately from several CFS criterias.

The Nightingale Research Foundation Definition

The Nightingale Research Foundation Definition, developed by Dr. Byron Hyde and published in 2007 with a later update, in 2016 represents a particularly disease-oriented interpretation of M.E.

It defines M.E. as an acute-onset infectious disease process and places considerable emphasis upon measurable CNS abnormalities.

Its conceptual model therefore differs substantially from CFS criterias constructed principally around unexplained chronic fatigue.

The Nightingale approach asks clinicians to investigate disease rather than merely count symptoms.

This can include investigation of neurological, vascular and other physiological abnormalities.

Whether every proposed biomarker or aetiological mechanism within the Nightingale framework ultimately proves sufficiently specific for routine diagnosis is a separate scientific question.

But the definition itself is plainly not interchangeable with Holmes, Fukuda or SEID.

The International Consensus Criteria (ICC)

The 2011 International Consensus Criteria represent another distinct criteria.

They abandoned chronic fatigue as the defining organising concept and instead made Post-Exertional Neuroimmune Exhaustion (PENE) compulsory.

The ICC additionally require manifestations from neurological impairment categories, which include:

neurocognitive impairment;
pain;
sleep disturbance;
neurosensory/perceptual/motor disturbance;

alongside immune, gastrointestinal/genitourinary and energy-production/transport abnormalities.

The latter include manifestations involving:

cardiovascular function,
respiratory function,
temperature regulation,
and intolerance of temperature extremes.

This gives ICC a substantially broader neurological and systemic phenotype than SEID.

There is consequently significant phenomenological overlap between ICC manifestations and symptoms that can occur in neurological infectious disease.

Again:

overlap does not prove identical pathology.

But it demonstrates why patients selected under ICC cannot automatically be assumed to be interchangeable with patients selected under a much narrower symptom algorithm.

The Ramsay, Nightingale and ICC overlap is different from CFS Criteria Overlap

The diagram therefore contains at least two different kinds of overlap.

One is overlap among fatigue-based CFS definitions.

Another is overlap among definitions attempting to capture a more extensive neurological/systemic M.E. phenotype.

Ramsay, Nightingale and ICC are themselves not identical definitions.

They should not be presented as though they are.

But they share considerably greater emphasis upon neurological, motor, autonomic, sensory and systemic abnormalities than minimalist fatigue-based definitions.

This distinction is important when analysing research cohorts.

A cohort selected according to Ramsay-like neurological characteristics cannot automatically be assumed to be biologically equivalent to a cohort selected by Fukuda CFS.

And neither can automatically be assumed equivalent to a SEID cohort.

SEID is a Fundamentally Different Algorithm

The 2015 IOM/SEID criteria substantially simplify the clinical requirements.

The core requirements are essentially:

**substantial impairment with fatigue

post-exertional malaise
unrefreshing sleep
cognitive impairment and/or orthostatic intolerance.**

This is visible in the diagram: the SEID box occupies only a comparatively small group of the manifestations represented by the broader neurological definitions.

That does not make SEID “wrong” as a case definition.

But it makes it different.

SEID does not require:

motor disturbance,
muscle weakness,
photophobia,
flu-like symptoms,
sore throat,
lymphadenopathy,
myalgia,
temperature dysregulation,
gastrointestinal symptoms,
genitourinary dysfunction,
or the broader neurological phenotype represented elsewhere in the diagram.

Consequently, somebody can satisfy SEID without reproducing either the historical Ramsay presentation, or the broader ICC phenotype.

The SEID algorithm can capture patients with other Diseases

This is where diagnostic minimisation becomes a legitimate concern.

The fewer disease-specific manifestations an algorithm requires, the greater the importance of rigorous differential diagnosis.

Fatigue, PEM, poor sleep, cognitive difficulty and orthostatic intolerance can occur in numerous diseases.

Therefore, the algorithm cannot determine by itself whether those symptoms result from:

neurological disease,
cardiovascular disease,
autonomic disease,
endocrine disease,
sleep disease,
post-infectious disease,
medication effects,
or another pathological process.

Indeed, published work comparing case definitions has repeatedly shown that different definitions select substantially different populations.

This means SEID must not be treated as a substitute for differential diagnosis.

Testing can change the Diagnosis

This is crucial.

The original 1988 Holmes definition itself required other clinical conditions capable of producing the fatigue to be excluded through history, physical examination and appropriate laboratory investigation.

The 1994 Fukuda criteria likewise requires clinically evaluated unexplained fatigue and specifically calls for investigation of differential diagnoses where indicated.

Therefore, testing is not somehow contrary to these definitions.

Testing is precisely how an explanatory disease may be discovered.

Depending upon the presentation, disease-directed investigation may include:

MRI brain and spinal cord;
lumbar puncture and CSF analysis;
pathogen-specific PCR;
appropriately timed enterovirus testing;
EMG and nerve-conduction studies;
autonomic testing;
cardiac investigation;
and other targeted investigations.

In specialist or research contexts concerning suspected persistent enteroviral disease, additional approaches have included enterovirus neutralising antibodies, cerebral perfusion SPECT and gastrointestinal biopsy investigation for enteroviral VP1, although these answer different questions and do not carry the same diagnostic weight as demonstrating an acute CNS infection.

The essential principle remains:

AN ALGORITHM CANNOT OVERRULE AN EXPLANATORY DISEASE DISCOVERED THROUGH APPROPRIATE INVESTIGATION.

Long COVID adds yet another Overlapping Population

Long COVID now complicates this landscape further.

Patients following SARS-CoV-2 infection can experience:

fatigue,
post-exertional worsening,
cognitive impairment,
sleep disturbance,
orthostatic intolerance,
palpitations,
temperature abnormalities,
myalgia,
headache,
gastrointestinal symptoms,
sensory disturbances,
and neurological complaints.

It is therefore unsurprising that many Long-COVID patients can satisfy criteria developed for ME/CFS.

But this establishes criteria overlap, not necessarily disease identity.

A Long-COVID patient may have separately diagnosable:

PoTS,
myocarditis,
pericarditis,
pulmonary disease,
neuropathy,
vascular disease,
endocrine dysfunction,
or another post-infectious complication.

Calling all of these manifestations “ME/CFS symptoms” risks losing useful diagnostic precision.

The Central Problem is Diagnostic Compression

The successive definitions can create a process of diagnostic compression.

A complex disease presentation containing:

**infectious onset

neurological abnormalities
motor dysfunction
autonomic dysfunction
sensory abnormalities
cardiovascular manifestations**

can gradually become reduced to:

**fatigue

PEM
poor sleep
cognitive problems.**

That reduction may make an algorithm easier to administer.

But easier classification is not necessarily better disease identification.

The information discarded by the algorithm may be precisely the information required to distinguish one disease from another.

Separate the Definitions

For clarity, the definitions should therefore be discussed separately rather than presented as interchangeable stages in the evolution of one diagnosis.

1. Holmes CFS - 1988

A Chronic Fatigue Syndrome working case definition explicitly created as a syndrome of unknown cause.

It required prolonged debilitating fatigue, exclusion of alternative causes and a large number of associated symptoms.

Its symptom list contained a striking infectious-like phenotype:

fever/chills, sore throat, painful lymph nodes, myalgia, muscle weakness, headache, joint pain and rapid onset, alongside neurological/neuropsychological manifestations.

It therefore overlaps symptomatically with many infectious illnesses, including features that can occur during the systemic phase of enterovirus infection.

It is not proof of enteroviral disease.

2. Fukuda CFS - 1994

A broader CFS research definition centred upon clinically evaluated, unexplained chronic fatigue plus four of eight accompanying symptoms.

Unlike Holmes, it reduced the number of required associated manifestations substantially.

The symptoms include:

memory/concentration impairment, sore throat, tender lymph nodes, muscle pain, joint pain, headache, unrefreshing sleep and PEM.

Again, these manifestations are nonspecific.

3. Ramsay M.E.

Ramsay's M.E. description emphasises a different clinical conception:

acute onset, characteristic muscle fatigability with delayed recovery of muscle power, neurological disturbance, fluctuation and a prolonged/relapsing course.

It should therefore not simply be renamed Fukuda CFS or SEID.

4. Nightingale Research Foundation Definition

The Nightingale Definition describes M.E. as an acute-onset infectious disease process and places emphasis upon objective CNS and physiological abnormalities.

This is explicitly a disease-oriented framework rather than simply an unexplained-fatigue algorithm.

It has substantial conceptual overlap with the neurological disease model associated with Ramsay, although the two definitions should not be treated as word-for-word identical.

5. International Consensus Criteria - 2011

ICC requires PENE and a broad range of neurological, immune, gastrointestinal/genitourinary, autonomic, cardiovascular, respiratory and thermoregulatory manifestations.

Its neurological categories explicitly include neurosensory, perceptual and motor disturbances.

Its phenotype is therefore considerably broader than SEID.

Again, ICC and Ramsay/Nightingale should not simply be declared identical, but there is substantial overlap in the emphasis placed upon neurological and systemic dysfunction.

6. IOM/SEID - 2015

SEID reduces the required phenotype principally to:

**functional impairment/fatigue

PEM
unrefreshing sleep
cognitive impairment and/or orthostatic intolerance.**

It does not reproduce the complete Ramsay phenotype.

It does not reproduce the complete Nightingale framework.

It does not reproduce the ICC phenotype.

And those symptoms can occur in multiple other illnesses.

SEID should therefore be understood as its own clinical criteria framework, not proof that every patient meeting it has the same underlying disease.

7. Long COVID/Post-COVID Condition

Long COVID is yet another post-infectious clinical category, this time defined by its relationship to SARS-CoV-2.

Its symptoms can overlap substantially with CFS, SEID and contemporary ME/CFS criterias.

But Long COVID can also contain identifiable organ-specific sequelae.

Therefore:

Long COVID ≠ automatically CFS.

Long COVID ≠ automatically SEID.

Long COVID ≠ automatically Ramsay M.E.

And symptom overlap with M.E. criteria does not establish that SARS-CoV-2 and enteroviruses produce identical neurological pathology.

What the Diagram Should Really Teach Us?

The diagram should not be interpreted as evidence that medicine has progressively discovered better names for one homogeneous disease.

It demonstrates something more complicated:

THE PATIENT POPULATION CHANGES WHEN THE DEFINITION CHANGES.

Holmes selects one population.

Fukuda selects another.

Oxford can select another.

CCC changes the phenotype.

ICC changes it again.

Ramsay represents a different historical disease description.

Nightingale represents a disease-oriented M.E. definition.

SEID dramatically compresses the required manifestations.

Long COVID then introduces a huge SARS-CoV-2-associated population with symptoms overlapping several of them.

If all these groups are subsequently called “ME/CFS”, clinically and biologically different patients can become indistinguishable on paper.

The Research Consequence: Heterogeneous Cohorts

This creates a major research problem.

Suppose one study recruits Fukuda CFS.

Another recruits SEID.

Another recruits ICC.

Another recruits self-reported ME/CFS.

Another recruits Long-COVID patients who happen to satisfy an ME/CFS questionnaire.

If researchers then treat all five populations as biologically interchangeable, apparent contradictions become almost inevitable.

A biomarker present in a narrowly defined neurological subgroup may disappear in a broad fatigue cohort.

A treatment response confined to one pathological mechanism may appear ineffective when tested across heterogeneous patients.

An infectious association may disappear.

And an abnormality belonging primarily to Long COVID may be incorrectly generalised to historical M.E.

That is case-definition heterogeneity and cohort contamination, not necessarily evidence that the underlying disease has no measurable pathology.

Conclusion

The overlap shown in the definitions diagram is real.

But its significance has been repeatedly misunderstood.

The 1988 Holmes CFS definition contains an infectious-like onset phenotype including fever, sore throat, lymph-node tenderness, muscle weakness, myalgia, headache and rapid onset. Those manifestations overlap with symptoms that can occur during enteroviral infection and with the minor illness associated with poliovirus infection.

That overlap does not prove that Holmes CFS was enteroviral disease.

It demonstrates why symptom-based criteria cannot identify a pathogen.

Likewise, neurological manifestations of enteroviral encephalitis, brainstem encephalitis or encephalomyelitis can overlap superficially with symptoms subsequently appearing in M.E., the ME/CFS criteria or the SEID algorithm.

But an acute infectious neurological disease requires disease-directed investigation.

Ramsay M.E., the Nightingale Research Foundation Definition and ICC place substantially greater emphasis upon neurological, motor, autonomic and systemic abnormalities than the minimalist SEID algorithm, although these three frameworks are themselves not identical.

The SEID algorithm captures a smaller set of highly nonspecific manifestations and therefore places particularly heavy responsibility upon clinicians to identify alternative explanatory diseases.

Long COVID adds still another heterogeneous post-infectious population with substantial symptom overlap.

The appropriate conclusion is therefore not:

“They all have the same symptoms, so they are all the same disease.”

It is:

“THEY SHARE SYMPTOMS. NOW FIND OUT WHICH DISEASE THE PATIENT ACTUALLY HAS.”

Anorexia or feeding difficulty requires explanation.

Muscle weakness requires neurological characterisation.

Motor disturbance requires localisation.

Cognitive impairment may require investigation of the brain - including limbic or other relevant structures depending on the presentation.

Cranial-nerve, swallowing, autonomic or respiratory abnormalities may point towards brainstem involvement.

Flaccid weakness may require investigation of the spinal cord, anterior horn cells or peripheral motor system.

Myocarditis and pericarditis require cardiac diagnosis rather than being reduced to post-viral fatigue.

And where acute enteroviral CNS disease is suspected, MRI, lumbar puncture with CSF analysis and appropriately timed PCR and other disease-directed investigations can matter far more than whether the patient happens to satisfy a fatigue algorithm.

SYMPTOM OVERLAP IS A REASON FOR BETTER DIFFERENTIAL DIAGNOSIS - NOT A REASON TO COLLAPSE DISTINCT DISEASES INTO ONE LABEL.

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"SEID" WAS A PROPOSED REPLACEMENT FOR THE CFS (“ME/CFS”) CONSTRUCT - NOT A DEFINITION OF HISTORICAL "MYALGIC ENCEPHALOMYELITIS"

The problem with conflating SEID ("ME/CFS"), Myalgic Encephalomyelitis, Enteroviral Encephalomyelitis and Long COVID

There is a fundamental historical and diagnostic distinction that is frequently lost in modern discussions of Systemic Exertion Intolerance Disease (SEID), Chronic Fatigue Syndrome (CFS), “ME/CFS” and Myalgic Encephalomyelitis (M.E.).

SEID was not created as a new definition of historical Ramsay "Myalgic Encephalomyelitis".

In 2015, the US Institute of Medicine (IOM) was commissioned to develop new clinical diagnostic criteria for the disorder being referred to as “ME/CFS.”

The committee concluded that the name Chronic Fatigue Syndrome should no longer be used and proposed a new name:

Systemic Exertion Intolerance Disease (SEID).

Crucially, the IOM also considered the name Myalgic Encephalomyelitis and rejected it as the appropriate name for the population it had reviewed.

The committee argued that there was insufficient evidence to characterise that population as having encephalomyelitis and that myalgia was not sufficiently central to the illness.

Whatever one thinks of the IOM's reasoning, this establishes an important historical fact:

SEID was a proposed replacement name and new clinical framework for the CFS (“ME/CFS”) construct being considered by the IOM.

It was NOT a demonstration that "Chronic Fatigue Syndrome" was historical Myalgic Encephalomyelitis or "Enteroviral Encephalomyelitis".

This distinction matters enormously.

"SEID" IS NOT AN ENCEPHALOMYELITIS DIAGNOSIS

The IOM's SEID criteria centre principally on:

a substantial reduction in ability to function accompanied by fatigue;
post-exertional malaise (PEM);
unrefreshing sleep; and
cognitive impairment and/or orthostatic intolerance.

These manifestations can be disabling.

But they are not specific for encephalomyelitis.

"SEID" does not require evidence of:

encephalitis;
myelitis;
encephalomyelitis;
CNS infection;
brainstem inflammation;
spinal-cord disease;
cranial-nerve palsies;
lower-motor-neurone involvement;
objective muscle weakness;
abnormal reflexes;
CSF inflammation;
characteristic MRI abnormalities; or
enteroviral infection.

This is because SEID was not constructed as a diagnostic definition of enteroviral encephalomyelitis.

A SEID misdiagnosis asks whether somebody satisfies a particular clinical symptom pattern.

An enteroviral encephalomyelitis diagnosis asks a completely different question:

Does this patient have an enterovirus-associated inflammatory neurological disease involving the brain and spinal cord?

These are not interchangeable diagnostic propositions.

THE HISTORICAL SEQUENCE MATTERS

The terminology is easier to understand when the chronology is kept intact.

1988 - Holmes "Chronic Fatigue Syndrome" (CFS)

The Holmes working case definition introduced CFS as a syndrome centred on otherwise unexplained chronic fatigue accompanied by a collection of other symptoms.

1994 - Fukuda "Chronic Fatigue Syndrome"

The CDC revised the CFS research definition, again retaining unexplained chronic fatigue as its central feature.

Over subsequent years, the terminology increasingly became written as CFS/ME or ME/CFS, effectively joining two historically different names.

2011 - International Consensus Criteria (ICC) for M.E.

The ICC authors explicitly criticised the CFS terminology and attempted to define M.E. using a substantially broader neurological and multi-system phenotype.

2015 - IOM/SEID

The IOM reviewed the literature and patient population conventionally described as “ME/CFS”, rejected Chronic Fatigue Syndrome as an inadequate name, rejected Myalgic Encephalomyelitis as an appropriate name for that population, and proposed:

Systemic Exertion Intolerance Disease (SEID).

It is therefore historically misleading to present the sequence as:

M.E. (also known as Enteroviral Encephalomyelitis) → ME/CFS → SEID

as though medicine merely changed the name of one unchanged neurological disease.

A more accurate chronology recognises that CFS was created as a syndrome, later became linguistically joined to M.E. as “ME/CFS”, and the IOM subsequently proposed SEID as a replacement designation for the disorder it had been asked to examine.

THE “ME/CFS” SLASH CREATES THE CONFLATION

The hybrid term ME/CFS encourages a misleading chain of equivalence:

M.E. (also known as Enteroviral Encephalomyelitis) = CFS

therefore:

M.E. (also known as Enteroviral Encephalomyelitis) = ME/CFS

therefore:

ME/CFS = SEID

therefore:

M.E. (also known as Enteroviral Encephalomyelitis) = SEID.

But the final conclusion does not follow.

Indeed, the IOM's own reasoning demonstrates the problem.

If the committee believed that the population it reviewed had established Myalgic Encephalomyelitis, there would have been little reason to reject that name because encephalomyelitis had supposedly not been adequately demonstrated.

The committee instead proposed a new name based upon a characteristic it considered central:

"exertion intolerance".

Therefore, describing SEID retrospectively as though it were simply a new diagnostic definition of Ramsay M.E. obscures what the IOM actually did.

"RAMSAY M.E." PREDATES CFS AND SEID

Historical descriptions of Myalgic Encephalomyelitis associated with Melvin Ramsay predate both Chronic Fatigue Syndrome and the SEID algorithm by decades.

Ramsay's clinical descriptions emphasised features including:

acute infectious onset;
neurological disturbance;
characteristic muscle fatigability;
delayed restoration of muscle power;
marked fluctuation; and
a prolonged or relapsing course.

Whatever conclusions are ultimately reached about the pathology and aetiology of historical Ramsay M.E., it cannot simply be back-defined by diagnostic criteria invented decades later for CFS.

A 2015 algorithm cannot retrospectively determine what disease Ramsay was describing.

THE NIGHTINGALE RESEARCH FOUNDATION DEFINITION IS ALSO DIFFERENT

The Nightingale Research Foundation Definition, associated with Dr. Byron Hyde, takes a disease-oriented approach to M.E. and explicitly distinguishes M.E. from CFS.

It places substantially greater emphasis upon an acute infectious onset and objective neurological and physiological abnormalities than the IOM/SEID algorithm.

Whether every proposed investigation or biomarker within the Nightingale framework ultimately proves sufficiently specific is a separate scientific question.

But conceptually the difference is clear:

Nightingale attempts to identify and characterise a disease process.

SEID identifies a clinical pattern using a small group of symptoms and functional abnormalities.

These approaches should not be presented as interchangeable.

ICC AND THE SEID ALGORITHM ARE NOT THE SAME CRITERIA

The International Consensus Criteria (ICC) make the distinction even clearer.

The 2011 ICC paper was explicitly titled:

“Myalgic encephalomyelitis: International Consensus Criteria.”

The authors rejected chronic fatigue as an adequate organising concept and required Post-Exertional Neuroimmune Exhaustion (PENE) together with manifestations across multiple neurological and physiological domains.

ICC includes substantially greater emphasis upon:

neurocognitive abnormalities;
pain;
sleep abnormalities;
neurosensory disturbances;
perceptual abnormalities;
motor disturbances;
immune manifestations;
gastrointestinal and genitourinary manifestations;
autonomic abnormalities;
cardiovascular abnormalities;
respiratory abnormalities; and
temperature dysregulation.

SEID does not require this complete phenotype.

A patient can therefore satisfy SEID without satisfying ICC.

The two definitions cannot legitimately be treated as identical.

LUCINDA BATEMAN'S INVOLVEMENT ILLUSTRATES THE DISTINCTION

Dr. Lucinda Bateman was an author of the 2011 International Consensus Criteria.

She subsequently served on the 2015 IOM committee that developed the new clinical criteria and proposed the SEID terminology.

These were two different criteria-development exercises.

ICC attempted to define M.E. using a comparatively extensive neurological and multi-system phenotype.

The IOM subsequently developed a much simpler clinical framework for the disorder it had been commissioned to examine as "ME/CFS" and proposed renaming it SEID.

The fact that some experts participated in both exercises does not make the resulting definitions identical.

It demonstrates precisely why the name of the criteria being used must always be stated.

"ENTEROVIRAL ENCEPHALOMYELITIS" IS A DIFFERENT DIAGNOSTIC CATEGORY

The distinction becomes particularly important when discussing enteroviral encephalomyelitis.

An established enteroviral encephalomyelitis is an infectious neurological diagnosis.

Depending upon the anatomical distribution and severity, enteroviral CNS disease can involve:

the cerebral hemispheres;
limbic structures;
brainstem;
cerebellum;
spinal cord;
motor pathways; and
autonomic structures.

A patient may consequently develop manifestations such as:

headache;
photophobia;
confusion or cognitive impairment;
seizures;
altered consciousness;
myoclonic jerks;
ataxia;
diplopia;
cranial-nerve palsies;
facial weakness;
dysarthria;
dysphagia;
autonomic instability;
asymmetric limb weakness;
acute flaccid weakness or paralysis;
altered reflexes;
bladder or bowel dysfunction; or
respiratory impairment.

Some of these manifestations may overlap with symptoms appearing in CFS, ICC or SEID criteria.

That does not transform enteroviral encephalomyelitis into SEID.

It demonstrates that different diseases can share symptoms.

BRAINSTEM AND LIMBIC DISEASE ILLUSTRATE WHY “BRAIN FOG” IS INADEQUATE

Neurological localisation is lost when complex neurological abnormalities are compressed into generic terminology such as “brain fog”.

For example, involvement of limbic structures may produce:

memory impairment;
confusion;
behavioural abnormalities;
seizures; and
other disturbances of cognition.

Brainstem involvement may produce:

cranial-nerve palsies;
abnormal eye movements;
diplopia;
facial weakness;
dysarthria;
dysphagia;
autonomic instability; and
respiratory dysfunction.

Calling all of this “cognitive impairment” or “fatigue” destroys clinically important information.

Neurological signs should be localised and investigated.

ANOREXIA AND FEEDING PROBLEMS ALSO REQUIRE DIFFERENTIAL DIAGNOSIS

The term anorexia in infectious and neurological medicine means loss of appetite; it does not necessarily mean anorexia nervosa.

Enteroviral illness can be associated with poor appetite and gastrointestinal symptoms.

Severe neurological disease can additionally interfere with feeding through:

nausea;
loss of appetite;
altered consciousness;
bulbar dysfunction;
dysphagia; or
inability to swallow safely.

In infants and young children, severe enteroviral disease may manifest with poor feeding.

In adults, prolonged inadequate intake or dysphagia can result in weight loss and nutritional problems.

Again, these findings require investigation of their cause rather than being reduced to a generic fatigue symptom.

AN EXPLANATORY NEUROLOGICAL DISEASE SHOULD NOT BE REPLACED BY SEID

This is the central clinical issue.

A patient with an established neurological disease may also happen to experience:

fatigue + PEM + unrefreshing sleep + cognitive impairment + orthostatic intolerance.

That does not make the neurological diagnosis disappear.

If an infectious encephalomyelitis adequately explains the clinical presentation, the explanatory disease should be diagnosed and managed as such.

A symptom algorithm cannot overrule objective pathology.

This distinction is particularly important in acute presentations.

A patient developing:

altered consciousness;
seizures;
new cranial-nerve abnormalities;
dysphagia;
acute asymmetric weakness;
flaccid paralysis;
rapidly progressive neurological abnormalities; or
respiratory compromise

requires urgent neurological assessment.

Such a patient should not simply be placed into a fatigue-management pathway while waiting to satisfy a chronic-duration criterion.

TESTING CAN DISTINGUISH AN EXPLANATORY DISEASE FROM A SYMPTOM CONSTRUCT

The SEID (ME/CFS) algorithm cannot demonstrate encephalomyelitis.

Disease-directed investigation may provide evidence for or against specific neurological diagnoses.

Depending upon presentation and timing, investigation can include:

detailed neurological examination;
MRI of the brain and spinal cord;
lumbar puncture;
CSF cell count, protein and glucose;
pathogen-specific CSF PCR where appropriate;
appropriately timed enterovirus PCR from relevant specimens;
EMG and nerve-conduction studies where motor abnormalities are present;
autonomic investigations;
cardiac investigations where indicated; and
other targeted investigations based upon the differential diagnosis.

Other specialist or research investigations discussed in relation to possible persistent enteroviral disease have included neutralising-antibody studies, cerebral perfusion SPECT and gastrointestinal biopsy investigation for enteroviral VP1.

These investigations have different purposes, limitations and evidential weight and should not be treated as interchangeable with proof of acute CNS infection.

The general principle, however, is straightforward:

Testing can potentially identify an explanatory disease that a symptom algorithm cannot.

SEID CAN PRODUCE DIAGNOSTIC COMPRESSION

Consider a patient whose actual presentation is:

**acute infectious onset

photophobia
cranial-nerve palsy
diplopia
dysphagia
myoclonic jerks
asymmetric flaccid weakness
autonomic dysfunction
cognitive impairment
profound exertional deterioration.**

If this is compressed to:

**fatigue

PEM
unrefreshing sleep
cognitive impairment
orthostatic intolerance,**

much of the neurological phenotype has disappeared.

That is the danger of applying SEID as though it were an explanation for the disease rather than a description of a particular symptom pattern.

Simplification can become diagnostic minimisation.

LONG COVID: THE SAME CONFLATION IS NOW HAPPENING AGAIN

Long COVID introduces another large and heterogeneous post-infectious population into this already confused terminology.

Many people following SARS-CoV-2 infection experience:

fatigue;
post-exertional symptom exacerbation;
cognitive impairment;
sleep disturbance;
orthostatic intolerance;
palpitations;
headache;
myalgia;
gastrointestinal symptoms; and
autonomic abnormalities.

Some Long-COVID patients will consequently satisfy the SEID algorithm or other ME/CFS criteria.

That is unsurprising because the criteria contain many of the same symptoms.

But this demonstrates criteria overlap.

It does not automatically demonstrate disease identity.

LONG COVID → SEID DOES NOT MEAN LONG COVID → RAMSAY M.E.

A misleading chain of reasoning can occur:

Long COVID

↓

patient satisfies SEID

↓

SEID is labelled ME/CFS

↓

ME/CFS is treated as synonymous with M.E. (also known as Enteroviral Encephalomyelitis)

↓

therefore:

Long COVID = M.E. (also known as Enteroviral Encephalomyelitis)

The final conclusion does not follow from the preceding observations.

What has actually been demonstrated is much narrower:

Some Long-COVID patients have a symptom phenotype that satisfies the SEID algorithm/CFS-type criteria.

That does not demonstrate that they have:

enteroviral infection;
encephalomyelitis;
Ramsay M.E.;
Nightingale-defined M.E.; or
the same underlying pathology as another post-infectious population.

LONG COVID CAN ITSELF CONTAIN SPECIFIC DIAGNOSABLE DISEASES

This distinction is especially important because SARS-CoV-2 can be followed by specific organ pathology.

A patient may have:

myocarditis;
pericarditis;
cardiac dysfunction;
pulmonary disease;
PoTS or another autonomic disorder;
neuropathy;
vascular complications;
endocrine abnormalities; or
neurological complications.

These diseases can themselves produce fatigue, exertional intolerance, cognitive symptoms or orthostatic symptoms.

For example:

myocarditis can cause fatigue and exercise intolerance.

PoTS can cause orthostatic intolerance and cognitive difficulty.

sleep disorders can cause fatigue and unrefreshing sleep.

neurological disease can cause cognitive impairment and reduced exertional capacity.

A patient may therefore resemble SEID because another disease is generating symptoms contained in the SEID algorithm.

That is why differential diagnosis matters.

SYMPTOM OVERLAP DOES NOT ESTABLISH SHARED PATHOLOGY

If researchers recruit Long COVID patients who have:

fatigue + PEM + cognitive impairment + unrefreshing sleep

and then observe that those symptoms resemble SEID (ME/CFS), the overlap is real.

But some of that overlap is inherent in the way the groups have been defined.

It does not independently establish identical:

pathology;
neuroanatomy;
infectious aetiology;
immune mechanisms;
biomarkers;
natural history; or
treatment response.

Those questions require biological investigation.

THE DEFINITIONS MUST BE KEPT SEPARATE

For clarity, these categories should be identified explicitly rather than collapsed into the hybrid term “ME/CFS”:

Holmes CFS (1988)

Fukuda CFS (1994)

Ramsay Definition for M.E. (1986 & 1988)

Canadian Consensus Criteria (CCC) (2003)

International Consensus Criteria M.E. (2011)

IOM/SEID - "ME/CFS" (2015)

Nightingale Research Foundation Definition for M.E. (2007 & 2016)

Long COVID/Post-COVID Condition (2020)

specific diagnosed enteroviral CNS disease

They can overlap.

A patient might satisfy more than one definition.

But overlapping sets are not automatically identical diseases.

CONCLUSION

SEID needs to be understood in its correct historical context.

The IOM did not demonstrate that Chronic Fatigue Syndrome was Myalgic Encephalomyelitis.

It was commissioned to address the disorder being called "ME/CFS", rejected Chronic Fatigue Syndrome as an appropriate name, also rejected Myalgic Encephalomyelitis as an appropriate name for the population it had reviewed, and proposed Systemic Exertion Intolerance Disease instead.

Therefore:

"SEID" WAS A PROPOSED REPLACEMENT NAME AND NEW CLINICAL FRAMEWORK FOR THE CFS (“ME/CFS”) CONSTRUCT - NOT A NEW DEFINITION OF HISTORICAL RAMSAY "MYALGIC ENCEPHALOMYELITIS" AND NOT A DIAGNOSIS OF "ENTEROVIRAL ENCEPHALOMYELITIS".

Ramsay M.E., the Nightingale Research Foundation Definition, ICC, CFS and SEID should therefore be examined separately rather than retrospectively collapsed into one disease through the hybrid label “ME/CFS”.

An established enteroviral encephalomyelitis is a specific neurological diagnosis. If it explains a patient's illness, the presence of fatigue, PEM, sleep disturbance, cognitive impairment or orthostatic intolerance does not transform it into SEID.

The same principle applies to Long COVID.

Long COVID can overlap with the SEID algorithm, without thereby becoming historical M.E.

The logical error is:

symptom overlap → criteria overlap → assumed disease identity.

The scientifically defensible approach is:

DEFINE THE CONDITIONS SEPARATELY.

INVESTIGATE EXPLANATORY DISEASE.

IDENTIFY THE PATHOLOGY WHERE POSSIBLE.

THEN STUDY THE OVERLAP.

A symptom algorithm can describe a phenotype.

It cannot, by itself, establish a pathogen, demonstrate encephalomyelitis, localise a neurological lesion, or prove that historically distinct disease concepts are biologically identical.

SYMPTOM OVERLAP IS NOT DISEASE IDENTITY.

"SEID" IS NOT PROOF OF ENCEPHALOMYELITIS.

AND LONG COVID MEETING SEID ALGORITHM IS NOT, BY ITSELF, PROOF OF RAMSAY M.E.