Sudden Onset "Myalgic Encephalomyelitis" (also known as Enteroviral Encephalomyelitis) is NOT Chronic Fatigue Syndrome, ME/CFS, the SEID Algorithm, Functional Neurological Disorder (FND) or Long COVID
Ramsay M.E., Acute "Enteroviral Encephalomyelitis" and FND: Diagnostic Confusion in Clinical Practice and A&E
Introduction
A serious diagnostic problem can arise when Ramsay Myalgic Encephalomyelitis (M.E.) or an acute enteroviral neurological disease is confused with Chronic Fatigue Syndrome (CFS), the Systemic Exertion Intolerance Disease (SEID) algorithm, medically unexplained symptoms, or Functional Neurological Disorder (FND).
These diagnoses and diagnostic constructs are not interchangeable.
Most importantly:
Acute enteroviral encephalomyelitis is an infectious neurological disease. It is not Chronic Fatigue Syndrome and it is not defined by the SEID symptom algorithm.
When a patient presents to Accident & Emergency (A&E) following an acute infectious illness with neurological abnormalities - such as asymmetric flaccid weakness, cranial-nerve palsies, diplopia, facial paralysis, dysphagia, altered reflexes, autonomic disturbance or respiratory involvement - the priority must be to investigate the neurological disease.
Profound exhaustion may accompany neurological infection.
Cognitive impairment may accompany neurological infection.
Orthostatic disturbance may accompany neurological infection.
Activity may worsen neurological symptoms.
None of these observations converts encephalitis or encephalomyelitis into CFS or SEID.
Symptom overlap does not establish disease equivalence.
Ramsay M.E. is NOT simply Chronic Fatigue Syndrome
One of the fundamental problems in contemporary clinical practice is the assumption that:
M.E. = CFS = ME/CFS = SEID.
Historically, these terms arose from different definitions, and different concepts of disease.
A. Melvin Ramsay's description of Myalgic Encephalomyelitis was not simply a description of unexplained chronic tiredness.
Ramsay emphasised neurological disturbance, characteristic muscle fatigability, delayed restoration of muscle power following exertion, marked fluctuation and a prolonged or relapsing course.
The later term Chronic Fatigue Syndrome, by contrast, was constructed around diagnostic criteria identifying patients principally through prolonged fatigue and associated symptoms after specified alternative explanations had been considered.
Conflating the two can erase clinically important neurological history.
This distinction was strongly emphasised by Dr. Byron Hyde and the Nightingale Research Foundation.
The Nightingale Research Foundation Definition
The Nightingale Research Foundation Definition of Myalgic Encephalomyelitis deliberately distinguishes M.E. from Chronic Fatigue Syndrome.
Its approach is disease-oriented rather than simply symptom-algorithm-oriented.
The underlying clinical question is not merely:
“Does this patient satisfy a fatigue checklist?”
It is:
“What disease occurred, what organs and neurological structures have been affected, and what objective abnormalities can be demonstrated?”
That distinction becomes especially important when illness begins with an acute infectious neurological event.
Under this approach, the history of acute neurological disease cannot simply disappear because the patient subsequently develops a prolonged disability.
Nor should the presence of chronic exhaustion cause the original neurological disease to be retrospectively reclassified as CFS.
Acute Enteroviral Encephalomyelitis is a Neurological Disease
Enteroviruses are capable of causing recognised neurological disease.
Depending upon the virus, anatomical involvement and individual presentation, enteroviral neurological disease can include:
- aseptic meningitis;
- encephalitis;
- encephalomyelitis;
- brainstem encephalitis;
- myelitis;
- acute flaccid paralysis; and
- poliomyelitis-like neurological disease.
Consequently, a patient developing neurological abnormalities during or shortly after an enteroviral illness may require investigation for disease affecting the brain, brainstem, spinal cord, anterior horn cells, cranial nerves, nerve roots or peripheral nervous system.
Possible clinical manifestations include:
- headache;
- neck pain or stiffness;
- photophobia;
- fever or preceding febrile illness;
- gastrointestinal or respiratory illness;
- altered cognition;
- profound CNS exhaustion;
- abnormal muscle fatigability;
- asymmetric weakness;
- flaccid limb weakness;
- altered tendon reflexes;
- cranial-nerve palsies;
- abnormal ocular movements;
- diplopia;
- facial palsy;
- dysarthria;
- dysphagia;
- autonomic dysfunction;
- bladder or gastrointestinal dysautonomia; and
- respiratory impairment.
The presence of several anatomically meaningful neurological abnormalities should immediately move the clinical discussion beyond the generic concept of “fatigue”.
Acute Enteroviral Encephalomyelitis is NOT "CFS"
An acute enteroviral encephalomyelitis diagnosis and a CFS misdiagnosis answer fundamentally different clinical questions.
Encephalomyelitis identifies inflammatory neurological disease involving the brain and spinal cord.
CFS criterias classify a prolonged clinical presentation according to specified criteria.
If investigation identifies a neurological disease that adequately explains the patient's illness, that diagnosis matters, and is excluded.
This is particularly important for CFS criterias containing medical exclusions. Under such criterias, identification of an active medical or neurological disease capable of explaining the patient's "fatigue" can "exclude" a CFS "misdiagnosis".
Therefore, diagnostic investigation is not peripheral to the distinction.
Testing can identify the neurological disease that prevents an erroneous CFS misclassification with M.E.
Acute Enteroviral Encephalomyelitis is NOT the SEID Algorithm
The same principle applies to the Systemic Exertion Intolerance Disease (SEID) criteria proposed by the US Institute of Medicine in 2015.
SEID was proposed as a diagnostic framework for the condition the IOM addressed as ME/CFS. Its core criteria concern substantial impairment lasting more than six months accompanied by fatigue, post-exertional malaise, unrefreshing sleep and cognitive impairment and/or orthostatic intolerance.
That algorithm does not diagnose acute encephalitis.
It does not diagnose encephalomyelitis.
It does not diagnose meningitis.
It does not identify an enterovirus.
It does not localise a cranial-nerve lesion.
It does not explain acute asymmetric flaccid paralysis.
It does not determine why a patient has developed dysphagia.
And it cannot substitute for neurological examination, microbiological investigation, neuroimaging or cerebrospinal-fluid analysis.
The 2015 SEID algorithm framework does not operate with exactly the same exclusion list as older CFS criterias. Nevertheless, the presence of another disease that adequately explains the patient's symptoms is fundamental to differential diagnosis.
Consequently, testing capable of identifying an explanatory neurological disease matters greatly when determining whether CFS or SEID is an appropriate label.
Testing Can Reveal the Disease Hidden Behind a Symptom Label
One of the most damaging misconceptions is:
“The tests were normal, therefore nothing neurological is wrong.”
A more appropriate question is:
Which tests were performed, when were they performed, what anatomical or pathological process were they capable of detecting, and were the appropriate investigations performed for the suspected disease?
Routine A&E investigations represent only a fraction of neurological investigation.
A normal full blood count does not exclude encephalomyelitis.
A normal metabolic panel does not exclude cranial neuropathy.
A normal CT scan does not exclude every inflammatory, infectious, brainstem, spinal-cord or peripheral neurological disease.
And normal structural imaging does not diagnose FND.
When the clinical history suggests infectious neurological disease, disease-directed investigation is required.
MRI of the Brain and Spinal Cord
Magnetic Resonance Imaging (MRI) can be an important investigation where encephalitis, encephalomyelitis, myelitis, brainstem disease or another central neurological process is suspected.
Depending upon the presentation, imaging may need to include:
brain, brainstem and spinal cord.
MRI can investigate structural and inflammatory abnormalities that may not be visible on routine CT imaging.
However, a normal MRI must still be interpreted in clinical context.
MRI sensitivity depends upon the disease, anatomical location, timing, imaging sequences and pathological process involved.
A normal MRI is not equivalent to a diagnosis of FND.
Lumbar Puncture and Cerebrospinal-Fluid Investigation
Where clinically appropriate, lumbar puncture (LP) can provide direct information about inflammatory or infectious processes affecting the central nervous system.
CSF investigation may include:
- white-cell count;
- red-cell count;
- protein;
- glucose;
- differential cell count;
- microbiological testing;
- oligoclonal bands or other inflammatory studies where indicated; and
- pathogen-specific molecular testing.
When acute enteroviral CNS infection is suspected, enterovirus RT-PCR of cerebrospinal fluid may provide direct molecular evidence of enteroviral infection.
Timing matters.
A negative PCR result does not invariably prove that an infection never occurred. Viral load, specimen timing, anatomical compartment, assay characteristics and previous evolution of the infection all influence diagnostic yield.
Nevertheless, in an appropriate acute presentation, CSF PCR is fundamentally different from assuming that neurological symptoms are functional because routine tests are unrevealing.
Enterovirus PCR From Other Specimens
Depending upon the suspected enterovirus, clinical presentation and timing, molecular testing may also involve appropriate stool, throat or respiratory specimens.
This can be especially relevant because enteroviruses may be detectable at different sites at different stages of infection.
The significance of a positive result must always be interpreted alongside the neurological presentation.
Detection of enterovirus outside the CNS does not automatically prove that the virus is causing encephalomyelitis.
But neither should potentially relevant microbiological evidence be disregarded merely because neurological imaging is unrevealing.
Clinical diagnosis depends upon assembling the entire evidential picture.
Enterovirus Neutralising Antibodies
Neutralising-antibody testing represents another potential component of enterovirus investigation in selected circumstances.
Testing can look for serotype-specific neutralising antibodies and, where appropriately timed specimens are available, changes in antibody titre.
Interpretation requires caution.
A single elevated antibody titre does not independently prove active CNS infection.
Results depend upon:
- timing;
- serotype tested;
- previous exposure;
- laboratory methodology;
- titre;
- paired versus single specimens; and
- the clinical context.
Nevertheless, neutralisation testing may contribute additional evidence when interpreted alongside the infectious history, neurological findings and other investigations.
It should neither be treated as definitive in isolation nor dismissed as irrelevant.
VP1 Gastric and Intestinal Biopsies
Another area requiring careful distinction is enteroviral VP1 testing of gastrointestinal biopsy tissue.
Research by John Chia and colleagues reported enteroviral VP1 protein detected by immunohistochemistry in gastric biopsy specimens from a substantial proportion of patients studied with CFS compared with controls.
This work contributed to a hypothesis of persistent enterovirus within gastrointestinal tissue in a subgroup of chronically ill patients.
VP1 immunohistochemistry is therefore relevant when discussing research into possible enteroviral persistence.
However, its evidential role must be stated accurately.
A VP1-positive gastric biopsy is not, by itself, a standard diagnostic test proving acute enteroviral encephalomyelitis.
It concerns a different biological question: evidence potentially compatible with enteroviral material or persistence within gastrointestinal tissue.
Where clinically or scientifically relevant, gastrointestinal tissue investigation may include immunohistochemistry and molecular methods.
But this should be distinguished from CSF enterovirus PCR during suspected acute CNS infection.
The investigations are complementary in concept; they are not diagnostically equivalent.
SPECT Cerebral Perfusion Imaging
The Nightingale Research Foundation approach has placed particular emphasis on cerebral perfusion imaging, including SPECT.
Systems such as Segami OASIS/NeuroGam can be used to process and quantitatively analyse cerebral perfusion SPECT data.
SPECT may demonstrate regional patterns of altered cerebral perfusion that are not necessarily apparent on structural CT or conventional MRI.
This illustrates an important principle:
Structural imaging and functional/perfusion imaging measure different things.
A structurally normal MRI does not logically establish that cerebral physiology is normal.
Nevertheless, cerebral perfusion SPECT should be described according to the strength of the available evidence. It is not an independently definitive test proving acute enteroviral encephalomyelitis.
Within the Nightingale framework, however, SPECT perfusion abnormalities form part of a broader disease-oriented investigation rather than a fatigue questionnaire.
That distinction is relevant to the argument.
Electrophysiology and Flaccid Weakness
Where a patient develops significant flaccid weakness, electromyography (EMG) and nerve-conduction studies (NCS) may help determine whether abnormalities involve:
- anterior horn cells;
- motor axons;
- peripheral nerves;
- nerve roots;
- neuromuscular transmission; or
- muscle.
Again, timing can influence findings.
The clinical examination remains essential.
A patient with genuine acute flaccid weakness should not simply be labelled as having “functional weakness” without appropriate assessment of the motor system.
Cranial-Nerve Abnormalities Require Anatomical Localisation
Cranial-nerve abnormalities are particularly important because they can provide anatomical clues.
CN VI - Abducens nerve
A right sixth-nerve palsy impairs abduction of the right eye.
The affected eye may consequently deviate medially towards the nose, producing esotropia and horizontal diplopia.
CN VII - Facial nerve
A lower-motor-neurone facial palsy may cause:
- forehead weakness;
- incomplete eye closure;
- flattening of the nasolabial fold;
- drooping of the affected corner of the mouth; and
- impaired facial movement.
If cranial-nerve abnormalities occur together with flaccid limb weakness, dysphagia or other neurological abnormalities, clinicians should consider the anatomical relationship between the brainstem, cranial nerves, spinal cord and peripheral motor system.
These findings require neurological reasoning.
They cannot be explained simply by saying that a patient is tired.
Dysphagia and Bulbar Dysfunction are Red Flags
Dysphagia during an acute neurological illness requires particular attention.
It can indicate involvement of the brainstem, cranial nerves or bulbar motor pathways.
It may also lead to:
- aspiration;
- dehydration;
- malnutrition;
- inability to take medication safely; and
- respiratory complications.
Where swallowing safety is uncertain, formal assessment may be required.
A patient presenting with flaccid weakness plus dysphagia plus cranial-nerve abnormalities requires serious neurological assessment regardless of whether initial routine investigations are normal.
Where FND can be incorrectly Introduced?
Functional Neurological Disorder is a recognised neurological diagnosis.
The problem is not the existence of FND.
The problem is using FND as the default explanation for neurological abnormalities that have not yet been adequately investigated.
Modern FND practice describes FND as a rule-in diagnosis supported by positive clinical features, rather than a diagnosis reached solely because other investigations are normal.
Therefore:
Normal blood tests ≠ FND.
Normal CT ≠ FND.
Normal MRI ≠ FND.
Psychiatric history ≠ FND.
Anxiety ≠ FND.
Unexplained symptoms ≠ FND.
The diagnosis requires its own clinical evidence.
Positive FND Signs do not Exclude Neurological Disease
Another crucial principle is that FND and organic neurological disease can coexist.
Even if a clinician demonstrates a genuinely positive functional neurological sign, that does not prove that every other neurological abnormality is functional.
A patient with FND can still develop:
encephalitis,
encephalomyelitis,
meningitis,
myelitis,
cranial neuropathy,
stroke,
peripheral neuropathy,
anterior-horn-cell disease,
or another neurological disorder.
Therefore, new neurological abnormalities require fresh assessment.
The Danger of Diagnostic Overshadowing
Once “FND” or even “ME/CFS” appears prominently in a patient's medical record, subsequent clinicians may unconsciously interpret new abnormalities through that label.
This can produce a dangerous sequence:
Previous diagnostic label
↓
New neurological abnormality
↓
Assumed to be part of previous diagnosis
↓
Reduced investigation
↓
No alternative disease discovered
↓
Lack of diagnosis treated as confirmation of the original label
This is circular reasoning.
It is not positive evidence.
The same problem can occur when an acute neurological illness becomes retrospectively rewritten as “ME/CFS”.
A documented history of acute neurological abnormalities may disappear and be replaced by a much less specific narrative:
“Patient developed fatigue after a virus.”
Those histories are not equivalent.
Testing can Exclude an inappropriate CFS or SEID Classification
This is why investigation matters so much.
A patient should not simply be asked whether they have:
fatigue,
post-exertional worsening,
unrefreshing sleep,
cognitive impairment,
or orthostatic intolerance
without first considering whether a diagnosable disease explains those symptoms.
Appropriate investigation may establish:
enteroviral encephalitis,
enteroviral encephalomyelitis,
aseptic meningitis,
myelitis,
acute flaccid paralysis,
poliomyelitis-like neurological disease,
cranial neuropathy,
peripheral neuropathy,
another infection,
an inflammatory neurological disease,
a metabolic disorder,
or another explanatory diagnosis.
Under exclusion-based CFS criterias, such an explanatory active disease can exclude an inappropriate CFS misdiagnosis.
The IOM/SEID framework handles exclusions differently from older CFS criteria, but an alternative disease capable of explaining the patient's symptoms remains central to proper differential diagnosis.
The existence of a symptom algorithm does not remove the obligation to diagnose an explanatory disease.
Disease-Directed Investigation Versus Algorithmic Diagnosis
This produces two very different approaches.
Disease-directed neurological investigation
Acute infectious illness
↓
Neurological abnormalities
↓
Detailed neurological examination
↓
Anatomical localisation
↓
MRI brain/spinal cord where indicated
↓
Lumbar puncture and CSF studies
↓
Enterovirus PCR or other pathogen testing where clinically appropriate
↓
Additional throat/stool/respiratory PCR where appropriate
↓
Neutralising-antibody testing in selected circumstances
↓
EMG/NCS for motor abnormalities
↓
SPECT cerebral perfusion investigation in specialised contexts
↓
VP1 gastrointestinal biopsy research/specialist investigation where relevant to persistence
↓
Integration of clinical, neurological, microbiological and physiological evidence
↓
Diagnosis of the underlying disease where possible
That is fundamentally different from:
Premature symptom classification
Viral illness
↓
Exhaustion
↓
Post-exertional worsening
↓
Cognitive symptoms
↓
CFS/SEID symptom algorithm
↓
Neurological abnormalities remain unexplained
↓
Routine tests normal
↓
FND
The second pathway risks losing the underlying neurological disease.
Different Tests Answer Different Questions
It is also essential not to pretend that all of these investigations have the same diagnostic weight.
They do not.
CSF enterovirus PCR addresses whether enteroviral RNA can be demonstrated in cerebrospinal fluid during the relevant illness.
MRI investigates structural and inflammatory abnormalities.
SPECT examines cerebral perfusion rather than viral identity.
EMG/NCS investigates physiological abnormalities within motor and peripheral nervous systems.
Neutralising antibodies provide immunological evidence requiring contextual interpretation.
VP1 gastrointestinal immunohistochemistry has been investigated as evidence relevant to possible tissue persistence and does not independently prove acute CNS infection.
A scientifically responsible investigation therefore asks:
What question is this test capable of answering?
rather than:
Was something abnormal somewhere?
This distinction strengthens, rather than weakens, the case for comprehensive neurological investigation.
The Correct Approach in A&E
When a patient arrives following an acute infectious illness with neurological abnormalities, the clinical sequence should be:
1. Establish the infectious and neurological chronology.
2. Perform a complete neurological examination.
3. Document objective abnormalities accurately.
4. Anatomically localise the disease process where possible.
5. Identify immediate neurological red flags.
6. Construct an appropriate infectious, inflammatory and neurological differential diagnosis.
7. Perform disease-directed investigations.
8. Reassess as the illness evolves.
9. If FND remains a consideration, identify positive clinical evidence supporting FND.
10. Do not allow FND, CFS, “ME/CFS” or SEID terminology to prevent investigation of new neurological signs.
The Central Diagnostic Error
The fundamental error is equating:
not yet explained
with
functional.
They are not synonymous.
Similarly:
fatigue after infection
is not synonymous with
CFS.
And:
post-exertional deterioration
is not synonymous with
SEID.
An explanatory disease discovered through MRI, lumbar puncture, PCR, electrophysiology, microbiology or other appropriate investigation changes the diagnostic picture.
The purpose of investigation is precisely to discover such diseases.
Conclusion
Acute enteroviral encephalomyelitis is an infectious neurological disease. It is not Chronic Fatigue Syndrome and it is not the SEID symptom algorithm.
Ramsay Myalgic Encephalomyelitis must likewise not simply be collapsed into the later CFS construct when discussing the historical disease described by Ramsay or the disease-oriented approach of the Nightingale Research Foundation Definition.
Most importantly, neurological investigation must come before premature functional attribution.
Where clinically appropriate, investigation may extend beyond routine A&E blood tests and CT imaging to include:
MRI of the brain and spinal cord;
lumbar puncture with CSF analysis;
enterovirus RT-PCR;
appropriate stool, throat or respiratory PCR;
enterovirus neutralising antibodies;
EMG and nerve-conduction studies;
cerebral perfusion SPECT, including specialised quantitative analysis such as Segami OASIS/NeuroGam;
and, in the appropriate research or specialist context, gastrointestinal biopsy investigation for enteroviral VP1.
These investigations do not all answer the same question and should not be presented as diagnostically equivalent. But collectively they demonstrate why “routine tests were normal” is not a sufficient basis for abandoning investigation of an organic neurological disease.
Testing can identify an explanatory disease.
An explanatory disease can prevent inappropriate classification under exclusion-based CFS criterias, and is essential to determining whether a SEID-type misdiagnosis is appropriate.
FND must meanwhile be supported by its own positive clinical evidence.
Therefore, when an acutely ill patient presents with an infectious onset followed by cranial-nerve palsies, asymmetric flaccid weakness, abnormal ocular movements, facial palsy, dysphagia, altered reflexes, autonomic dysfunction or respiratory involvement, the appropriate response is neurological localisation and disease-directed investigation.
Do not replace acute enteroviral encephalomyelitis with CFS.
Do not replace neurological disease with the SEID algorithm.
Do not allow “ME/CFS” terminology to erase the distinction made by the Nightingale Research Foundation approach.
Do not diagnose FND merely because initial routine investigations are normal.
INVESTIGATE THE NEUROLOGICAL DISEASE. IDENTIFY THE EXPLANATORY DIAGNOSIS. DO NOT ERASE IT WITH A SYMPTOM LABEL.
Long COVID or Another Diagnosable Disease?
Why Post-COVID Symptoms Must Not Replace the Diagnosis of a Specific Neurological, Cardiac, Pulmonary, Autonomic or Infectious Disease
Introduction
The term Long COVID has become an important way of recognising persistent illness following SARS-CoV-2 infection.
But it can also create a diagnostic problem if it is treated as the final explanation for every symptom occurring after COVID-19.
Long COVID is not a substitute for differential diagnosis.
A patient can develop neurological, cardiovascular, pulmonary, autonomic, inflammatory, thrombotic or other diseases during or following SARS-CoV-2 infection.
Those diseases should be diagnosed in their own right where the evidence supports them.
This principle is built into major definitions of Post-COVID Condition.
The World Health Organization defines Post-COVID Condition as occurring following probable or confirmed SARS-CoV-2 infection, usually around three months after onset, with symptoms lasting at least two months that cannot be explained by an alternative diagnosis.
NICE similarly defines Post-COVID-19 syndrome as symptoms developing during or following COVID-19, continuing for more than 12 weeks and not explained by an alternative diagnosis.
That qualification is crucial.
The diagnosis requires clinicians to consider what else could explain the patient's illness.
Long COVID is NOT Every Disease that Happens After COVID-19
Temporal association does not establish diagnostic identity.
A patient may develop symptoms after SARS-CoV-2 infection and genuinely have:
- myocarditis or pericarditis;
- pulmonary embolism;
- pulmonary disease;
- autonomic dysfunction such as PoTS;
- peripheral neuropathy;
- myositis;
- encephalitis or another inflammatory neurological disease;
- stroke or other cerebrovascular disease;
- endocrine or metabolic disease;
- another infection;
- another post-infectious neurological disease; or
- another independently diagnosable condition.
These diagnoses should not disappear underneath the words “Long COVID.”
WHO itself acknowledges that Post-COVID Condition can affect numerous organ systems and that cardiovascular, pulmonary and neurological sequelae occur following COVID-19.
Therefore the relevant clinical question is not simply:
“Did these symptoms begin after COVID?”
It is also:
“What disease or physiological abnormality is causing these symptoms?”
Long COVID is a Clinical Case Definition
This distinction matters.
WHO's definition does not require a single biomarker establishing one uniform pathological mechanism.
It is a clinical case definition developed through a Delphi consensus process.
Common manifestations include fatigue, breathlessness and cognitive dysfunction, but numerous other symptoms have been reported.
Symptoms may persist from the original infection, develop after apparent recovery, fluctuate or relapse.
This makes Long COVID clinically useful as an umbrella description.
But it also means that symptom overlap cannot establish the underlying pathology.
Fatigue does not identify a disease.
Brain fog does not identify a disease.
Breathlessness does not identify a disease.
Palpitations do not identify a disease.
Post-exertional deterioration does not identify a disease.
These manifestations can occur in multiple distinct medical conditions.
“Long COVID” Must NOT Become Diagnostic Closure
Consider a patient who develops COVID-19 and several months later reports:
Fatigue + breathlessness + tachycardia + dizziness + cognitive impairment.
It would be easy to call this Long COVID.
But those symptoms could justify investigating, depending upon the individual presentation:
PoTS or another autonomic disorder;
cardiac disease;
pulmonary disease;
anaemia;
endocrine disease;
thromboembolic disease;
neurological disease;
medication effects;
or other pathology.
Likewise:
COVID-19 + chest pain + exercise intolerance
should not automatically become Long COVID without considering cardiac and pulmonary causes.
And:
COVID-19 + focal neurological abnormalities
should not automatically become “Long COVID brain fog”.
Focal neurological signs require neurological reasoning.
Acute Neurological Disease is NOT “Long COVID”
Timing is particularly important.
NICE distinguishes:
Acute COVID-19 - up to 4 weeks
Ongoing symptomatic COVID-19 - 4 to 12 weeks
Post-COVID 19 Syndrome - more than 12 weeks, where symptoms are not explained by an alternative diagnosis.
WHO's Post-COVID Condition definition generally applies around three months following infection, with symptoms lasting at least two months and lacking an alternative explanation.
Therefore a patient developing an acute encephalitis, myelitis, stroke, cranial neuropathy or other defined neurological complication during COVID-19 should have that disease recognised.
It should not retrospectively disappear simply because persistent disability subsequently develops.
Long COVID and Ramsay M.E. must not automatically be conflated
Another increasingly important area of confusion concerns Long COVID and Myalgic Encephalomyelitis.
There can unquestionably be symptom overlap.
WHO notes that some patterns reported in Post-COVID Condition include PoTS, post-exertional malaise, and manifestations associated with the ME/CFS (SEID) symptom checklist.
But overlap does not establish identity.
Long COVID is defined by its temporal relationship with SARS-CoV-2 infection and the absence of a better alternative explanation.
Ramsay M.E. is a historical disease description that predates SARS-CoV-2 by decades.
The Nightingale Research Foundation Definition, associated with Dr. Byron Hyde, goes further and explicitly conceptualises M.E. as an acute-onset infectious disease process involving measurable CNS abnormalities.
Whether one accepts every proposed mechanism within that definition or not, it represents a substantially different disease concept from the WHO Post-COVID Condition case definition.
Therefore:
Long COVID ≠ automatically Ramsay M.E.
And:
Ramsay M.E. ≠ automatically Long COVID.
Patients must be evaluated according to the disease actually present.
SARS-CoV-2 does not EXCLUDE another infection
Another diagnostic trap is assuming that because a patient recently had SARS-CoV-2, every subsequent symptom must have been caused by SARS-CoV-2.
People can have more than one infection.
A patient can contract COVID-19 and subsequently acquire another viral, bacterial or other infectious disease.
Similarly, an illness initially assumed to have been COVID-19 may never have been microbiologically confirmed.
This becomes particularly important where the clinical presentation is unusual for uncomplicated COVID-19 or includes features suggestive of another infection.
Depending upon the clinical history, appropriate differential diagnosis may therefore include testing for other infectious agents.
Enteroviral Neurological Disease is a Differential Diagnosis, NOT Long COVID
If the clinical history suggests an enteroviral illness followed by neurological abnormalities, enterovirus should be considered according to the presentation.
Enteroviruses can cause recognised diseases including:
aseptic meningitis,
encephalitis,
encephalomyelitis,
myelitis,
brainstem disease,
acute flaccid paralysis,
and poliomyelitis-like neurological disease.
If an enteroviral neurological disease is established, the diagnosis should reflect that disease.
The fact that the illness occurred during the COVID era - or even after documented SARS-CoV-2 infection - does not transform "enteroviral encephalomyelitis" into Long COVID.
Neurological Red Flags Require Neurological Investigation
Particular caution is required where a patient labelled with Long COVID develops:
- asymmetric weakness;
- flaccid paralysis;
- abnormal reflexes;
- cranial-nerve palsies;
- diplopia;
- abnormal ocular movements;
- facial palsy;
- dysarthria;
- dysphagia;
- new bladder dysfunction;
- objective sensory abnormalities;
- seizures;
- altered consciousness; or
- significant respiratory muscle weakness.
These abnormalities should not simply be recorded as:
“Long COVID neurological symptoms.”
They may anatomically localise disease.
A sixth-nerve palsy, for example, has neurological significance.
A lower-motor-neurone facial palsy has neurological significance.
Flaccid limb weakness has neurological significance.
Dysphagia has neurological significance.
The clinician should ask:
Where is the lesion or physiological dysfunction?
and:
What disease could produce this pattern?
Disease-Directed Neurological Testing
Where the history and examination indicate neurological disease, investigation should follow the differential diagnosis rather than stop at the Long COVID label.
Depending upon the clinical circumstances, investigation may include:
MRI Brain and Spinal Cord
MRI may identify structural, inflammatory, vascular or other abnormalities involving the brain, brainstem or spinal cord.
A normal MRI does not establish that every neurological symptom is functional, nor does it prove that every symptom is Long COVID.
Lumbar Puncture
Where CNS infection or inflammation is suspected, cerebrospinal-fluid examination may include:
- cell count;
- protein;
- glucose;
- microbiological investigation;
- oligoclonal bands or other inflammatory studies where indicated; and
- pathogen-specific PCR.
Enterovirus RT-PCR
Where an acute enteroviral CNS infection is clinically suspected, CSF enterovirus RT-PCR may provide direct molecular evidence.
Depending upon the suspected infection and timing, stool, throat or respiratory PCR may also be appropriate.
A negative result must be interpreted according to timing, specimen type and the clinical context.
Enterovirus Neutralising Antibodies
Neutralising-antibody testing can provide additional evidence in selected circumstances.
Interpretation depends upon serotype, titre, timing, previous exposure, laboratory methodology and whether paired specimens are available.
A single titre does not independently establish CNS infection.
EMG and Nerve-Conduction Studies
Where the patient has flaccid weakness or suspected peripheral motor involvement, electrophysiology may help investigate abnormalities affecting anterior horn cells, motor axons, peripheral nerves, nerve roots, neuromuscular transmission or muscle.
Cerebral Perfusion SPECT and Segami OASIS/NeuroGam
The disease-oriented approach advocated by the Nightingale Research Foundation has placed particular emphasis upon cerebral perfusion abnormalities.
SPECT cerebral perfusion imaging, including quantitative processing systems such as Segami OASIS/NeuroGam, examines a different dimension of CNS function from conventional structural MRI.
MRI principally examines anatomy and structural pathology.
Perfusion SPECT evaluates patterns of cerebral blood flow.
The existence of normal structural imaging therefore does not logically establish normal cerebral perfusion.
However, these tests must be interpreted according to their evidential limitations.
SPECT perfusion abnormalities are not specific for one disease and cannot independently establish either enteroviral encephalomyelitis or Ramsay M.E.
Their relevance lies in adding physiological information to a broader disease-directed investigation.
Enteroviral VP1 Gastric or Intestinal Biopsy
Research has also investigated enteroviral VP1 protein in gastrointestinal biopsy tissue, particularly gastric tissue, in chronically ill patient groups.
This addresses a different question from acute CSF PCR.
CSF PCR seeks evidence of viral RNA in the context of CNS infection.
VP1 gastrointestinal immunohistochemistry investigates evidence potentially relevant to enteroviral material or persistence within gastrointestinal tissue.
Therefore:
VP1-positive gastrointestinal tissue does not independently prove acute enteroviral CNS infection.
But where clinically or scientifically appropriate, gastrointestinal tissue investigation may contribute to investigation of possible persistent enteroviral infection.
This should not be confused with either a Long COVID symptom checklist or a routine screening test.
Cardiac Disease Must Be Separated From Generic “Long COVID”
COVID-19 can affect the cardiovascular system.
Therefore persistent:
chest pain,
palpitations,
dyspnoea,
exercise intolerance,
syncope,
or tachycardia
should not automatically be attributed to a generic Long COVID diagnosis.
Depending upon the clinical presentation, evaluation may involve:
ECG,
cardiac biomarkers such as troponin,
echocardiography,
ambulatory rhythm monitoring,
or cardiac MRI.
The purpose is to determine whether the patient has an identifiable cardiovascular disease.
If myocarditis is demonstrated, then myocarditis is a diagnosis.
If pericarditis is demonstrated, then pericarditis is a diagnosis.
The fact that SARS-CoV-2 preceded it provides important aetiological context but does not make the specific diagnosis disappear.
Orthostatic Intolerance and PoTS
Dizziness, tachycardia, palpitations, weakness, cognitive difficulty and exercise intolerance can occur in Post-COVID Condition.
But these manifestations may also justify specific investigation for orthostatic intolerance or Postural Orthostatic Tachycardia Syndrome (PoTS).
Depending upon the clinical circumstances, investigation can include:
lying and standing heart rate and blood pressure,
active stand testing,
tilt-table testing,
ambulatory blood-pressure monitoring,
and autonomic testing.
If a patient fulfils appropriate diagnostic criteria for PoTS, that is clinically useful information.
It should not simply disappear into:
“Long COVID dizziness.”
Pulmonary and Thromboembolic Disease
Breathlessness is among the commonest symptoms reported in Post-COVID Condition.
But breathlessness also has a broad differential diagnosis.
Depending upon clinical circumstances, investigation may need to consider:
residual pulmonary disease,
pulmonary embolism,
cardiac disease,
anaemia,
respiratory muscle dysfunction,
autonomic dysfunction,
or another cause.
Again:
A symptom is the beginning of diagnostic reasoning—not necessarily its conclusion.
Long COVID and FND are also Different Diagnoses
The same safeguards apply to Functional Neurological Disorder.
A patient with persistent symptoms following COVID-19 should not automatically be diagnosed with FND because routine investigations are normal.
Nor should every neurological symptom automatically be attributed to Long COVID.
These represent different diagnostic possibilities requiring their own evidence.
The appropriate sequence is:
Neurological presentation
↓
Neurological examination
↓
Anatomical localisation
↓
Differential diagnosis
↓
Targeted investigation
↓
Specific disease diagnosis where demonstrated
↓
Only then determine what symptoms remain appropriately classified within Post-COVID Condition
This prevents both organic neurological disease and genuine FND from being diagnosed carelessly.
“Normal Routine Tests” Do Not End the Differential Diagnosis
A patient may be told:
“Your blood tests are normal.”
But which disease was being investigated?
Routine blood tests do not exclude every neurological disease.
A normal chest X-ray does not exclude every cardiopulmonary cause of breathlessness.
A normal CT does not exclude every neurological abnormality.
A normal MRI does not establish FND.
And none of these results automatically proves Long COVID.
The appropriate interpretation is:
“This investigation has not demonstrated the abnormality it was designed to detect.”
That is very different from:
“There is no disease.”
Testing Can Remove Patients From a Generic Long COVID Classification
This is particularly important because both the WHO and NICE definitions explicitly incorporate the absence of a better alternative diagnosis.
WHO states that Post-COVID Condition involves symptoms that cannot be explained by an alternative diagnosis.
NICE similarly defines Post-COVID-19 syndrome as signs and symptoms continuing beyond 12 weeks that are not explained by an alternative diagnosis.
Therefore, differential investigation is not an optional extra.
It is intrinsic to appropriate diagnosis.
If investigation identifies an alternative disease that explains the presentation, that finding matters.
Examples might include:
myocarditis instead of unexplained chest symptoms;
pulmonary embolism instead of unexplained breathlessness;
PoTS instead of unexplained orthostatic symptoms;
encephalitis instead of unexplained cognitive deterioration;
cranial neuropathy instead of unexplained visual or facial symptoms;
another infectious disease instead of presumed Post-COVID Condition.
A SARS-CoV-2 infection can still have preceded or even precipitated some of these conditions.
But the specific disease should still be named.
Long COVID can contain Multiple Diagnosable Diseases
There is another important possibility.
The choice does not always have to be:
Long COVID OR another disease.
Some patients may have Post-COVID Condition and one or more separately diagnosable sequelae or comorbid diseases.
For example:
Post-COVID Condition + PoTS
or
Post-COVID Condition + peripheral neuropathy
may be more clinically informative than treating every manifestation as one undifferentiated entity.
WHO acknowledges that Post-COVID Condition can affect numerous organ systems and that several biological mechanisms are under investigation.
The purpose of differential diagnosis is therefore not to deny Long COVID.
It is to make the diagnosis more precise.
The Diagnostic Pathway Should Be
Documented or probable SARS-CoV-2 infection
↓
Persistent/new symptoms
↓
Detailed chronology
↓
Physical and neurological examination
↓
Identify red flags
↓
Localise abnormalities where possible
↓
Construct differential diagnoses
↓
Perform targeted investigations
↓
Identify specific diseases and complications
↓
Treat those diseases appropriately
↓
Determine whether remaining unexplained manifestations satisfy an appropriate Post-COVID Condition definition
That is a disease-oriented approach.
Not This
COVID-19
↓
Persistent fatigue
↓
Brain fog
↓
PEM
↓
Dizziness
↓
“Long COVID”
↓
Stop investigating
That is precisely the diagnostic shortcut that the requirement to consider alternative diagnoses is intended to prevent.
Long COVID, CFS, SEID and Ramsay M.E. must NOT become one Diagnostic Bucket
The greatest danger is ultimately one of conflation.
A patient has COVID-19.
They remain ill.
They satisfy a broad Long COVID definition.
Their symptoms overlap with CFS.
They might satisfy SEID criteria.
They may also have post-exertional deterioration resembling descriptions used in contemporary ME/CFS (SEID) literature.
None of this establishes that:
Long COVID = CFS = SEID = Ramsay M.E.
These are different historical and diagnostic constructs.
The overlap may be scientifically important.
It may identify biologically meaningful subgroups.
Some patients may genuinely satisfy more than one diagnostic definition.
But that is a question for careful phenotyping and investigation - not an excuse to erase distinctions.
Conclusion
Long COVID is real, potentially severe and disabling.
But recognising Long COVID does not require abandoning differential diagnosis.
In fact, the opposite is true.
Both the WHO Post-COVID Condition definition and NICE Post-COVID-19 syndrome definition explicitly require consideration of alternative diagnoses.
A patient presenting after SARS-CoV-2 infection may have an identifiable:
neurological,
cardiac,
pulmonary,
autonomic,
vascular,
infectious,
inflammatory,
endocrine,
metabolic,
or other disease.
Where clinically indicated, appropriate investigation may therefore include MRI brain/spinal cord, lumbar puncture and CSF studies, pathogen-specific PCR, EMG/NCS, autonomic testing, ECG, echocardiography, cardiac MRI, pulmonary investigation and other disease-directed testing.
Where a separate enteroviral disease is genuinely suspected, investigation can additionally include appropriately timed enterovirus PCR and, in selected contexts, neutralising antibodies. Specialist/research approaches involving cerebral perfusion SPECT such as Segami OASIS/NeuroGam or gastrointestinal VP1 investigation answer different questions and should be interpreted according to their respective evidence and limitations.
The principle is simple:
COVID-19 can be the beginning of the diagnostic history without being the end of the diagnostic investigation.
Do not turn every neurological abnormality into “brain fog”.
Do not turn every cardiovascular abnormality into “Long COVID palpitations”.
Do not turn every autonomic disorder into “Long COVID dizziness”.
Do not automatically turn Long COVID into CFS, SEID or Ramsay M.E.
And do not stop looking for another disease simply because SARS-CoV-2 came first.
LONG COVID SHOULD PROMPT DIFFERENTIAL DIAGNOSIS - NOT REPLACE IT.
IDENTIFY THE UNDERLYING AND COEXISTING DISEASES WHEREVER THE EVIDENCE ALLOWS.
Enteroviral or SARS-CoV-2 Myopericardial Disease?
Differential Diagnosis of Pericarditis, Myocarditis and Dilated Cardiomyopathy
Introduction
A patient presenting with pericarditis, myocarditis or myopericarditis after a viral illness should not automatically be assumed to have SARS-CoV-2-associated cardiac disease simply because COVID-19 is common or because the illness occurred during the COVID era.
Enteroviruses are well-established causes of viral myocarditis and can also be associated with pericardial disease. In particular, coxsackie B viruses and other enteroviruses have a longstanding association with myocarditis, and enteroviral myocarditis can progress from acute myocardial inflammation to chronic ventricular dysfunction and a dilated cardiomyopathy (DCM) phenotype in some patients.
The 2025 European Society of Cardiology guidelines continue to list enteroviruses among viruses associated with myocarditis and specifically describe enteroviruses such as coxsackieviruses and echoviruses as cytolytic viruses capable of injuring cardiomyocytes.
SARS-CoV-2 can also be associated with myocarditis and pericarditis.
The clinical problem is therefore not simply:
“Does the patient have viral myocarditis?”
It is also:
“What caused the myocarditis or pericarditis?”
That distinction can matter for diagnosis, prognosis, epidemiology and, in selected cases, treatment.
Myocarditis, Pericarditis and Myopericarditis Are Diagnoses - Not Viral Identifications
The first distinction is anatomical.
Myocarditis means inflammation involving the myocardium, the muscular layer of the heart.
Pericarditis means inflammation of the pericardium surrounding the heart.
Myopericarditis describes overlapping myocardial and pericardial inflammation.
These terms establish where the inflammatory cardiac disease is occurring.
They do not, by themselves, establish its cause.
The 2025 ESC guidelines emphasise that myocarditis and pericarditis can have both infectious and non-infectious aetiologies and that viruses remain important infectious causes.
Among those viruses, the guideline specifically lists enteroviruses and coronaviruses.
Therefore:
Myocarditis ≠ automatically COVID-19 myocarditis.
Pericarditis ≠ automatically COVID-19 pericarditis.
The aetiology requires separate consideration.
Enteroviruses are Established causes of Myocarditis
Enteroviral cardiac disease has been recognised for decades.
Particularly important are group B coxsackieviruses, although other enteroviruses can also be implicated.
The contemporary ESC myocarditis guideline describes enteroviruses such as coxsackieviruses and echoviruses as cytolytic viruses. In contrast with viruses that act predominantly through vascular or immune mechanisms, enteroviruses can infect and damage cardiomyocytes and provoke myocardial inflammatory infiltration.
This provides a biologically plausible pathway from:
acute enterovirus infection
↓
cardiomyocyte infection/injury
↓
acute myocarditis
↓
persistent inflammation and/or viral persistence in some patients
↓
ventricular remodelling
↓
left-ventricular dilatation and impaired systolic function
↓
dilated cardiomyopathy phenotype
That progression does not occur in every patient with enteroviral myocarditis, but the relationship between enteroviral myocarditis and subsequent DCM is well established in the myocarditis literature.
Historic molecular studies demonstrated enteroviral genomes in myocardial biopsy specimens from patients with both myocarditis and dilated cardiomyopathy, and reviews have specifically examined the relationship between persistent enterovirus infection, chronic myocarditis and DCM.
Enteroviral Myocarditis can progress to Dilated Cardiomyopathy
This point deserves particular emphasis.
Dilated cardiomyopathy can represent a downstream consequence of myocarditis.
The myocardium may initially become inflamed and injured. If sufficient myocardial damage occurs - or if myocardial inflammation persists - the ventricle may remodel.
The heart can become:
- enlarged;
- more spherical;
- less contractile;
- increasingly unable to generate an adequate stroke volume; and
- clinically associated with heart failure, arrhythmia or exercise intolerance.
The result can be a dilated cardiomyopathy phenotype with reduced ventricular systolic function.
Enteroviruses are historically important in precisely this context. Molecular studies using PCR and in-situ hybridisation have demonstrated enteroviral genetic material in myocardial tissue from some patients with acute myocarditis, chronic myocarditis and DCM.
Modern ESC guidance also recognises endomyocardial biopsy as important in selected patients with myocarditis and chronic cardiomyopathy, particularly because histology, immunohistology and molecular viral analysis can help distinguish inflammatory cardiomyopathy from non-inflammatory forms.
Therefore the clinical history:
acute viral illness → myocarditis → persistent ventricular dysfunction → ventricular dilatation
should trigger consideration of post-myocarditic dilated cardiomyopathy, not simply generic “post-viral fatigue”.
SARS-CoV-2 can also cause Myopericardial Disease
COVID-19 provides a genuine alternative viral context.
SARS-CoV-2 infection has been associated with myocardial and pericardial inflammation, and the European Society of Cardiology published a dedicated 2025 consensus statement on myopericardial complications following COVID-19 disease and vaccination.
The mechanisms may not always be identical to classical cytolytic enteroviral myocarditis.
The 2025 ESC guideline distinguishes enteroviruses - which can directly damage cardiomyocytes - from viruses including SARS-CoV-2 that may produce myocarditis through substantial immune-mediated and inflammatory mechanisms.
This is an important distinction because a temporal relationship with COVID-19 is not necessarily evidence of direct myocardial SARS-CoV-2 infection.
A patient can have:
SARS-CoV-2 infection followed by immune-mediated myocarditis
without demonstrable viral infection of cardiomyocytes.
The Central Differential: Which Infection Came First?
Clinical chronology is critical.
The history should establish:
What infection actually preceded the chest pain or myocardial injury?
For example:
Pattern suggesting an enteroviral illness
A preceding illness might include:
- hand, foot and mouth disease;
- vesicular oral or pharyngeal lesions;
- gastrointestinal illness;
- vomiting or diarrhoea;
- pleurodynia/Bornholm-type chest or upper abdominal pain;
- meningitic or neurological manifestations;
- recognised enterovirus exposure or outbreak; or
- laboratory evidence of enterovirus.
This does not prove that subsequent myocarditis is enteroviral, but it increases the relevance of enterovirus in the differential diagnosis.
Pattern suggesting acute SARS-CoV-2
The preceding illness might include:
- a contemporaneous positive SARS-CoV-2 PCR or antigen test;
- respiratory symptoms compatible with COVID-19;
- fever;
- sore throat;
- cough;
- anosmia or ageusia, particularly in earlier variants;
- known COVID-19 exposure; or
- another characteristic COVID-19 presentation.
Again, temporal proximity alone does not prove cardiac causation.
Do Not Infer the Cause From Symptoms Alone
The cardiac manifestations of enteroviral and SARS-CoV-2-associated myocarditis can overlap substantially.
Both can potentially produce:
- chest pain;
- dyspnoea;
- palpitations;
- tachycardia;
- exercise intolerance;
- raised troponin;
- ECG abnormalities;
- ventricular dysfunction;
- arrhythmias;
- myocardial oedema on cardiac MRI; and
- pericardial involvement.
Therefore, the cardiac phenotype alone generally cannot reliably tell the clinician which virus caused it.
That requires microbiological, molecular and clinical evidence.
ECG
An ECG is a fundamental initial investigation.
Myocarditis or myopericarditis can produce:
- ST-segment abnormalities;
- T-wave abnormalities;
- sinus tachycardia;
- AV conduction abnormalities;
- atrial or ventricular arrhythmias; or
- other non-specific abnormalities.
Pericarditis may produce typical diffuse ST elevation and PR depression, although not every patient demonstrates the textbook pattern.
An ECG can therefore support the diagnosis of inflammatory cardiac disease.
But:
ECG cannot reliably distinguish enteroviral myocarditis from SARS-CoV-2 myocarditis.
It identifies cardiac electrical consequences, not viral identity.
Troponin
High-sensitivity troponin I or T can provide evidence of myocardial injury.
Elevation is particularly relevant where myocarditis is suspected.
But troponin is not virus-specific.
Raised troponin may occur with:
enteroviral myocarditis,
COVID-associated myocarditis,
acute coronary syndrome,
pulmonary embolism,
tachyarrhythmia,
severe systemic illness,
and numerous other causes of myocardial injury.
Therefore:
Troponin tells you that myocardial injury may be occurring. It does not tell you which virus caused it.
Inflammatory Markers
CRP and ESR may support the presence of inflammation.
They may be particularly useful in pericarditis and systemic inflammatory illness.
Again, they do not differentiate the viral cause.
The CDC similarly recommends ECG, troponin and inflammatory markers in the initial evaluation of suspected myocarditis/pericarditis while emphasising assessment for potential alternative causes, including SARS-CoV-2 and enterovirus PCR where available.
Echocardiography
Echocardiography is central to assessing the structural and functional consequences of myocarditis.
It can identify:
- reduced left-ventricular ejection fraction;
- regional or global hypokinesia;
- ventricular dilatation;
- right-ventricular dysfunction;
- diastolic abnormalities;
- pericardial effusion;
- haemodynamic compromise; and
- progression towards a cardiomyopathic phenotype.
This becomes particularly important when investigating possible progression from myocarditis to dilated cardiomyopathy.
Serial echocardiography can demonstrate the evolution from an initially inflammatory myocardial illness to persistent:
LV dilatation + impaired systolic function.
However:
An echocardiogram cannot identify enterovirus or SARS-CoV-2 as the cause.
Cardiac MRI
Cardiovascular magnetic resonance (CMR) now plays a major role in the diagnosis of myocarditis.
The 2025 ESC guidelines describe CMR as a cornerstone of contemporary multimodality assessment because it can identify myocardial and pericardial injury, inflammation and fibrosis.
CMR can evaluate:
- myocardial oedema;
- tissue characteristics;
- late gadolinium enhancement;
- ventricular size;
- ventricular function;
- fibrosis/scar;
- pericardial inflammation; and
- pericardial effusion.
This can provide powerful evidence that myocarditis has occurred.
But there is another crucial distinction:
Cardiac MRI can diagnose the myocardial inflammatory phenotype much better than it can identify the responsible virus.
A CMR pattern compatible with myocarditis does not, by itself, prove:
enterovirus
or
SARS-CoV-2.
SARS-CoV-2 Testing
When COVID-19 is suspected as the preceding infection, evidence can include:
SARS-CoV-2 NAAT/PCR during acute infection or, depending upon timing and context, other virological evidence.
A positive SARS-CoV-2 PCR demonstrates SARS-CoV-2 infection.
It does not automatically demonstrate that SARS-CoV-2 caused the myocarditis.
The patient could theoretically have:
COVID-19 + myocarditis caused by another process
or even
COVID-19 + another concurrent viral infection.
Therefore microbiological evidence must be interpreted alongside chronology and cardiac findings.
Enterovirus PCR
Where enteroviral myocarditis is clinically suspected, enterovirus PCR can contribute important evidence.
The appropriate specimen depends upon the clinical stage and presentation.
Possible specimens may include:
- throat/respiratory samples;
- stool;
- blood in selected circumstances; and
- most importantly in specialised myocarditis investigation, myocardial tissue obtained by endomyocardial biopsy.
CDC clinical guidance specifically advises clinicians investigating myocarditis/pericarditis to consider other viral causes and cites enterovirus PCR alongside SARS-CoV-2 testing.
However, detection of enterovirus in stool or throat demonstrates infection or shedding at that site.
It does not by itself prove myocardial infection.
This is where myocardial tissue becomes particularly important.
Endomyocardial Biopsy: The Most Direct Aetiological Investigation
In selected myocarditis cases, endomyocardial biopsy (EMB) provides information unavailable from routine blood tests or imaging.
The 2025 ESC guideline states that EMB can identify:
- the histological type of myocarditis;
- inflammatory infiltrates;
- cardiomyocyte injury;
- necrosis;
- fibrosis; and
- in selected cases, the infectious aetiology.
Molecular analysis can then look directly for viral DNA or RNA in myocardial tissue using quantitative PCR.
The guideline specifically states that endomyocardial biopsy permits detection of viruses including enteroviruses using quantitative RT-PCR and in-situ hybridisation.
This provides a fundamentally different level of evidence from:
“The patient had a virus before the myocarditis.”
For example:
myocarditis on histology + enteroviral RNA in myocardial tissue
provides much stronger evidence for enterovirus-associated myocarditis than a remote positive antibody titre.
Viral PCR on Endomyocardial Biopsy
The 2025 ESC guideline specifically emphasises molecular analysis of endomyocardial tissue.
Where indicated, biopsy material may undergo:
qRT-PCR for enteroviruses and other relevant infectious agents.
Blood collected at the same time can also be analysed to help determine whether a positive myocardial PCR merely reflects systemic viraemia or contamination.
This distinction is essential.
Detection of viral genetic material inside myocardial tissue in the appropriate histological context is much closer to identifying a cardiac viral aetiology than serology alone.
Viral Serology Is Much Weaker Evidence
Serology requires considerable caution.
The contemporary ESC guideline explicitly states that routine viral serology is not recommended for diagnosing viral myocarditis, because blood antibody results correlate poorly with viral PCR findings from myocardial tissue.
Therefore:
Positive Coxsackie B antibodies ≠ automatically Coxsackie B myocarditis.
Likewise:
Positive SARS-CoV-2 antibodies ≠ automatically SARS-CoV-2 myocarditis.
Antibodies demonstrate prior immune exposure.
They do not necessarily establish the cause of myocardial inflammation.
Enterovirus neutralising antibodies
Enterovirus neutralisation testing can nevertheless provide useful contextual evidence in selected cases, particularly where a specific enterovirus is clinically suspected.
Interpretation depends upon:
- serotype;
- titre;
- timing;
- previous exposure;
- paired versus single samples; and
- the laboratory methodology.
A convincing rise in titre across appropriately timed paired specimens is more informative than one isolated positive result.
But neither replaces myocardial investigation when definitive aetiological determination is clinically necessary.
Dilated Cardiomyopathy is a Critical Follow-Up Diagnosis
The differential should not end when the acute myocarditis settles.
Some patients develop persistent cardiac dysfunction.
If serial imaging demonstrates:
persistent left-ventricular dilatation
plus
persistent impaired systolic function,
the patient may have developed a dilated cardiomyopathy phenotype.
This should be recognised and investigated.
The 2023 ESC cardiomyopathy guideline identifies endomyocardial biopsy with immunohistochemistry and viral genome identification as an important method for identifying myocardial inflammation in selected cardiomyopathy cases.
The 2025 myocarditis guideline likewise notes that EMB can be valuable in progressive or treatment-resistant chronic cardiomyopathy and can differentiate inflammatory cardiomyopathy from non-inflammatory cardiomyopathies.
Therefore a history of:
viral illness → myocarditis → persistent ventricular dysfunction → DCM
should trigger investigation of a possible inflammatory/post-myocarditic cardiomyopathy.
Enterovirus Persistence and Chronic Cardiac Disease
Enteroviruses deserve particular consideration because persistent enteroviral material has historically been investigated in chronic myocarditis and DCM.
PCR and in-situ hybridisation studies have demonstrated enteroviral genomic material in myocardial biopsy samples from subsets of patients with myocarditis and DCM.
This does not mean that every case of unexplained DCM is caused by enterovirus.
Modern cardiomyopathy evaluation must also consider:
- genetic cardiomyopathy;
- toxic causes;
- alcohol-related cardiomyopathy;
- autoimmune or inflammatory disease;
- other viruses;
- ischaemic disease;
- metabolic causes;
- tachycardia-mediated cardiomyopathy; and
- numerous other possibilities.
But enteroviral myocarditis remains a legitimate disease pathway to chronic inflammatory cardiomyopathy and DCM.
Pericarditis requires the same aetiological discipline
The same reasoning applies to pericarditis.
Typical acute pericarditis can produce:
- sharp pleuritic chest pain;
- worsening on lying flat;
- improvement sitting forward;
- pericardial rub;
- ECG abnormalities;
- raised inflammatory markers; and
- pericardial effusion.
The ESC notes that typical pain is often pleuritic, worsens lying down and improves when sitting up and leaning forward.
But once pericarditis has been recognised, aetiology remains a separate question.
Potential infectious causes include viruses.
A history of SARS-CoV-2 infection may support COVID-associated pericarditis.
An enteroviral illness may support enteroviral pericarditis.
Neither should simply be assumed without considering the entire clinical picture.
Historic molecular studies have even detected enterovirus RNA in some pericardial effusion samples, demonstrating that enteroviruses can be directly relevant to pericardial disease.
Myopericarditis can be mistaken for “Long COVID”
There is another contemporary diagnostic danger.
Suppose a patient develops:
viral infection → chest pain → tachycardia → breathlessness → profound exercise intolerance.
If those symptoms persist, they can easily be described generically as:
“Long COVID.”
But persistent symptoms do not establish the underlying cardiac diagnosis.
A patient may instead have:
ongoing myocarditis,
residual myocardial injury,
pericarditis,
recurrent pericarditis,
myopericarditis,
ventricular dysfunction,
arrhythmia,
or post-myocarditic dilated cardiomyopathy.
A history of COVID-19 should therefore prompt cardiac differential diagnosis rather than replace it.
A Practical Differential Investigation
The work-up should be driven by severity and presentation, but may include:
Cardiac injury and inflammation
- high-sensitivity troponin I/T;
- CRP and ESR;
- full blood count;
- renal and liver function;
- NT-proBNP/BNP when heart failure is suspected.
Electrical assessment
- 12-lead ECG;
- telemetry where indicated;
- Holter or longer ambulatory ECG monitoring for arrhythmias.
Structural and functional cardiac assessment
- transthoracic echocardiography;
- serial echocardiography where ventricular dysfunction is present;
- cardiac MRI.
Viral differential diagnosis
- contemporaneous SARS-CoV-2 PCR/NAAT where relevant;
- enterovirus PCR from clinically appropriate specimens;
- other respiratory-virus testing where indicated;
- carefully interpreted enterovirus neutralising antibodies in selected cases.
Advanced aetiological investigation
- endomyocardial biopsy in clinically appropriate higher-risk or unresolved cases;
- myocardial histology;
- immunohistochemistry;
- viral qRT-PCR on biopsy tissue;
- parallel blood PCR where required for interpretation.
Dilated cardiomyopathy evaluation
- serial LV dimensions and ejection fraction;
- cardiac MRI for fibrosis and remodelling;
- rhythm monitoring;
- coronary evaluation where indicated;
- genetic assessment where appropriate;
- endomyocardial biopsy in selected inflammatory/progressive cases.
The ESC's current approach is similarly presentation-driven and combines history, biomarkers, ECG, echocardiography, CMR and - in selected patients - endomyocardial biopsy.
The Evidence Hierarchy Matters
Not every positive viral test carries the same meaning.
A useful way to understand the distinction is:
Weak aetiological evidence
“Patient remembers having a viral illness.”
↓
Stronger
Documented acute SARS-CoV-2 or enterovirus infection at the relevant time.
↓
Stronger still
Compatible infection + objectively diagnosed myocarditis.
↓
More direct evidence
Compatible myocarditis + virus demonstrated in myocardial tissue in an appropriate histological context.
That hierarchy prevents the common error:
COVID occurred first → therefore every later cardiac abnormality is caused by COVID.
The same caution applies to enterovirus.
A positive stool PCR does not independently establish myocarditis.
A neutralising-antibody titre does not independently establish myocarditis.
The cardiac disease and its cause require evidence appropriate to the question.
The Key Differential
When myocarditis or pericarditis occurs following infection, the clinician should therefore distinguish:
Enterovirus-associated disease
Possible supporting evidence includes:
**compatible enteroviral prodrome
- documented enterovirus infection
- objective myocarditis/pericarditis
- where clinically indicated, myocardial viral genome detection.**
SARS-CoV-2-associated disease
Possible supporting evidence includes:
**documented acute COVID-19
- appropriate temporal relationship
- objective myocarditis/pericarditis
- exclusion of competing causes
- specialised tissue evidence in exceptional cases where required.**
Myocarditis of uncertain aetiology
Sometimes myocarditis is clearly established but the responsible trigger cannot be proven.
The correct diagnosis may then remain:
myocarditis - aetiology undetermined
rather than inventing a viral attribution that has not been demonstrated.
That uncertainty is scientifically preferable to diagnostic overreach.
Conclusion
Enteroviruses and SARS-CoV-2 can both be associated with myocarditis and pericarditis, but they should not be treated as interchangeable causes.
Enteroviruses - particularly coxsackieviruses and echoviruses - have a well-established association with myocardial inflammation and direct cardiomyocyte injury. Contemporary ESC guidance continues to recognise enteroviruses among important viral causes of myocarditis and describes them as cytolytic viruses.
Importantly, enteroviral myocarditis can be followed by chronic inflammatory myocardial disease and a dilated cardiomyopathy phenotype in some patients. Molecular studies have identified enteroviral genomes in myocardial tissue from subsets of patients with myocarditis and DCM.
SARS-CoV-2 can also be associated with myocarditis and pericarditis, and dedicated contemporary ESC guidance recognises COVID-related myopericardial disease.
The correct diagnostic sequence is therefore:
Diagnose the cardiac disease.
Then:
Investigate its cause.
Use ECG, troponin and inflammatory markers to identify cardiac injury and inflammation.
Use echocardiography to assess ventricular function, chamber dilatation and pericardial effusion.
Use cardiac MRI to characterise myocardial inflammation, injury and fibrosis.
Use appropriately timed SARS-CoV-2 and enterovirus testing where clinically indicated.
And in selected cases where establishing the inflammatory subtype or viral aetiology will materially affect management, consider endomyocardial biopsy with histology, immunohistochemistry and myocardial viral qRT-PCR in accordance with specialist cardiology guidance.
Most importantly:
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