"MYALGIC ENCEPHALOMYELITIS" & "ENTEROVIRAL DISEASE" RESEARCH ROADMAP (2026)

HISTORICAL "MYALGIC ENCEPHALOMYELITIS" & "ENTEROVIRAL DISEASE" RESEARCH ROADMAP (2026)

"Epidemic" Myalgic Encephalomyelitis

(also known as "Enteroviral Encephalomyelitis")


A Comprehensive Research, Diagnostic, Treatment, Repair, Education, Surveillance and Prevention Programme for Historical/Ramsay Myalgic Encephalomyelitis and Directly Related Enteroviral Disease

DIAGNOSTICS • RAPID TESTING • VIROLOGY • SEROTYPING • GENOMICS • EPIDEMIOLOGY • NEUROPATHOLOGY • PERSISTENCE • BRAIN PERFUSION • BLOOD VOLUME • NEUROLOGY • MOTOR-NEURON DISEASE • RADICULITIS • BRACHIAL-PLEXUS DISEASE • PERIPHERAL NEUROPATHY • DYSAUTONOMIA • NEUROGASTROENTEROLOGY • MUSCLE • CARDIOLOGY • VASCULAR DISEASE • ENDOCRINOLOGY • PANCREAS • IMMUNOLOGY • AUTOIMMUNITY • RHEUMATOLOGY • HAEMATOLOGY • MAST-CELL BIOLOGY • NUTRITION • ANTIVIRALS • IMMUNOGLOBULIN • PLASMAPHERESIS • IMMUNOADSORPTION • PRECISION IMMUNOMODULATION • NEUROINFLAMMATION • STEM CELLS • REGENERATION • EDUCATION • PATIENT GOVERNANCE • SURVEILLANCE • VACCINES • PREVENTION

MISSION

Establish a dedicated, fully ring-fenced national and international research, diagnostic, treatment, education, surveillance and prevention programme for Historical/Ramsay Myalgic Encephalomyelitis (M.E.), addressed within this proposed roadmap as a sudden-onset neurological disease associated with enteroviral infection and referred to within this roadmap as Enteroviral Encephalomyelitis, together with directly related enteroviral neurological, neuromuscular, muscular, cardiac, vascular, autonomic, peripheral-nerve, gastrointestinal, pancreatic, endocrine, immune-mediated, rheumatological, haematological, respiratory, mucocutaneous, neonatal and systemic disease.

The purpose of the roadmap is to create an integrated enterovirus research infrastructure capable of following the disease process from the first hours of infection to its long-term neurological and multisystem consequences.

The programme should investigate:

EXPOSURE

↓

ENTEROVIRUS INFECTION

↓

SPECIES

↓

SEROTYPE

↓

GENOME

↓

ENTRY SITE

↓

CELLULAR TROPISM

↓

ORGAN AND NEUROANATOMICAL TROPISM

↓

ACUTE VIRAL REPLICATION

↓

HOST ANTIVIRAL RESPONSE

↓

VIRAL CLEARANCE OR PERSISTENCE

↓

NEUROINFLAMMATION / VASCULAR INFLAMMATION / AUTOIMMUNITY

↓

AUTONOMIC / ENDOCRINE / METABOLIC CONSEQUENCES

↓

MOTOR / SENSORY / ORGAN DAMAGE

↓

DISABILITY

↓

BIOLOGY-MATCHED TREATMENT

↓

VIRAL CLEARANCE WHERE ACHIEVABLE

↓

CONTROL OF PATHOGENIC IMMUNITY

↓

MAINTENANCE OF NUTRITION AND PHYSIOLOGY

↓

NERVE / MUSCLE / VASCULAR / ORGAN REPAIR

↓

PREVENTION.

The programme must distinguish:

ESTABLISHED OR STRONGLY SUPPORTED ENTEROVIRUS DISEASE

from

PLAUSIBLE ENTEROVIRUS-ASSOCIATED OR POST-INFECTIOUS DISEASE REQUIRING PROSPECTIVE INVESTIGATION

from

EXPLORATORY ASSOCIATIONS THAT REQUIRE A SUBSTANTIALLY HIGHER EVIDENTIARY THRESHOLD.

The roadmap should not assume that every proposed manifestation is caused by enterovirus. It should establish whether the relationship is:

  • direct viral infection;
  • persistent viral infection;
  • persistent viral antigen;
  • secondary immune injury;
  • autoimmune disease;
  • vascular/endothelial injury;
  • autonomic dysfunction;
  • residual structural damage;
  • metabolic/endocrine consequences;
  • an unrelated comorbidity;
  • or a mixture of mechanisms.

CORE PROGRAMME CONTINUUM

PREVENT

↓

CATCH

↓

SAMPLE

↓

TEST

↓

TYPE

↓

SEQUENCE

↓

QUANTIFY

↓

LOCALISE

↓

MAP

↓

MEASURE

↓

TREAT

↓

FIND IT IF IT PERSISTS

↓

CHARACTERISE THE IMMUNE RESPONSE

↓

CONTROL DAMAGING INFLAMMATION

↓

REMOVE PATHOGENIC AUTOANTIBODIES WHERE INDICATED

↓

RESTORE ANTIVIRAL IMMUNITY WHERE DEFICIENT

↓

MAINTAIN NUTRITION

↓

RESTORE BLOOD VOLUME WHERE OBJECTIVELY REDUCED

↓

RESTORE CEREBRAL PERFUSION WHERE OBJECTIVELY IMPAIRED

↓

REGENERATE NERVES

↓

REPAIR MUSCLE, HEART, VASCULATURE AND OTHER ORGANS

↓

PREVENT THE NEXT CASE.

PART I — 100% RING-FENCED FUNDING

1. HISTORICAL/RAMSAY M.E. AND ENTEROVIRAL DISEASE FUNDING

All funding allocated through this proposed programme should remain specifically ring-fenced for:

  • Historical/Ramsay Myalgic Encephalomyelitis;
  • Enteroviral Encephalomyelitis;
  • acute enteroviral CNS disease;
  • chronic/persistent enterovirus;
  • meningitis;
  • meningoencephalitis;
  • encephalitis;
  • brainstem encephalitis;
  • rhombencephalitis;
  • encephalomyelitis;
  • myelitis;
  • acute flaccid myelitis;
  • poliomyelitis-like disease;
  • anterior-horn disease;
  • motor-root disease;
  • radiculitis;
  • brachial-plexus disease;
  • peripheral motor neuropathy;
  • GBS;
  • Miller Fisher syndrome;
  • cranial neuropathies;
  • small-fibre neuropathy;
  • large-fibre neuropathy;
  • autonomic neuropathy;
  • neurogenic GI dysfunction;
  • abnormal muscle fatigability;
  • myositis;
  • muscle wasting;
  • pleurodynia;
  • rhabdomyolysis;
  • myocarditis;
  • pericarditis;
  • myopericarditis;
  • cardiomyopathy;
  • vascular/endothelial disease;
  • cerebral-perfusion abnormalities;
  • objectively measured low blood volume;
  • pancreatic disease;
  • thyroid/endocrine abnormalities;
  • immune and autoimmune disease;
  • rheumatological disease;
  • haematological disease;
  • enteroviral respiratory disease;
  • HFMD and mucocutaneous disease;
  • adult systemic/sepsis-like disease;
  • neonatal systemic/sepsis-like disease;
  • rapid diagnostics;
  • persistent-infection diagnostics;
  • antiviral development;
  • immunoglobulin treatment;
  • plasmapheresis;
  • immunoadsorption;
  • precision immunomodulation;
  • anti-inflammatory development;
  • regenerative medicine;
  • stem-cell research;
  • organoids;
  • vaccines;
  • tissue banks;
  • registries;
  • medical education;
  • patient governance;
  • surveillance.

Scientifically required comparator groups may include separately defined CFS, ME/CFS, SEID, Long COVID, fibromyalgia, autoimmune disease, neurological disease, chronic pain populations and healthy controls.

Comparator cohorts should be analytically separate and should not redefine the primary Historical/Ramsay-M.E./enteroviral neurological cohort.

PART II — HISTORICAL/RAMSAY M.E. CASE ASCERTAINMENT

2. DEDICATED HISTORICAL/RAMSAY M.E. ASCERTAINMENT

Develop a prospective ascertainment protocol centred on the historically described neurological disease rather than selecting participants only by fatigue-defined or PEM-defined symptom algorithms.

Document:

  • sudden infectious onset;
  • fever;
  • acute viral prodrome;
  • meningitic symptoms;
  • encephalitic manifestations;
  • encephalomyelitic manifestations;
  • brainstem involvement;
  • cranial-nerve dysfunction;
  • spinal-cord involvement;
  • motor weakness;
  • asymmetric weakness;
  • paresis;
  • abnormal muscle fatigability;
  • sensory abnormalities;
  • autonomic dysfunction;
  • bulbar dysfunction;
  • swallowing abnormalities;
  • visual sensory disturbance;
  • auditory sensory disturbance;
  • vestibular disturbance;
  • cognitive neurological dysfunction;
  • bladder dysfunction;
  • bowel dysfunction;
  • recurrent neurological manifestations;
  • prolonged neurological disability;
  • acute enterovirus evidence where obtainable;
  • persistent enterovirus evidence where obtainable.

Research should prioritise prospective acute-phase investigation because the opportunity to directly identify a causative virus may diminish after the initial infection.

3. HISTORICAL OUTBREAK RECONSTRUCTION

Reconstruct:

Los Angeles 1934

↓

Akureyri 1948–49

↓

Royal Free 1955

↓

other historically described outbreaks

↓

Ramsay

↓

Dowsett

↓

subsequent neurological clusters.

Retrieve:

  • hospital records;
  • neurological examinations;
  • epidemic curves;
  • attack rates;
  • geographical clustering;
  • occupational clustering;
  • household transmission;
  • systemic prodromes;
  • meningitic findings;
  • motor abnormalities;
  • sensory abnormalities;
  • muscle findings;
  • autonomic abnormalities;
  • cranial-nerve abnormalities;
  • cardiac complications;
  • gastrointestinal manifestations;
  • laboratory investigations;
  • contemporaneous virology.

Where archived material survives, investigate with:

  • RT-PCR;
  • qPCR;
  • ddPCR;
  • viral sequencing;
  • viral-protein detection;
  • in-situ hybridisation;
  • metagenomics;
  • proteomics;
  • immune profiling.

PART III — ENTEROVIRUS SPECIES, SEROTYPES AND EPIDEMICS

4. COXSACKIE B1–B6

Create dedicated workstreams for:

CV-B1 • CV-B2 • CV-B3 • CV-B4 • CV-B5 • CV-B6.

Investigate CNS manifestations:

  • meningitis;
  • encephalitis;
  • encephalomyelitis;
  • brainstem disease;
  • spinal disease;
  • paralysis.

Investigate muscle manifestations:

  • acute myositis;
  • severe myalgia;
  • rhabdomyolysis;
  • pleurodynia/Bornholm disease;
  • inflammatory-myopathy mimics;
  • persistent muscle dysfunction.

Investigate cardiac manifestations:

  • pericarditis;
  • myocarditis;
  • myopericarditis;
  • arrhythmias;
  • conduction disease;
  • persistent myocardial infection;
  • dilated cardiomyopathy.

Investigate pancreatic manifestations:

  • pancreatitis;
  • recurrent pancreatitis;
  • pancreatic persistence;
  • beta-cell stress;
  • Type 1 diabetes mechanisms.

Investigate GI/lymphoid compartments:

  • stomach;
  • duodenum;
  • terminal ileum;
  • Peyer’s patches;
  • mesenteric nodes;
  • other lymphoid tissue.

Determine which Coxsackie B types show the greatest:

  • neurotropism;
  • myotropism;
  • cardiotropism;
  • pancreatotropism;
  • persistence potential;
  • propensity for immune-mediated sequelae.

5. ECHOVIRUS RESEARCH

Priority:

E4 • E6 • E9 • E11 • E18 • E30

plus newly emerging clinically important types.

Map:

OUTBREAK

↓

SEROTYPE

↓

GENOTYPE / WHOLE GENOME

↓

TISSUE TROPISM

↓

NEUROLOGICAL PHENOTYPE

↓

SYSTEMIC PHENOTYPE

↓

IMMUNE RESPONSE

↓

CLEARANCE OR PERSISTENCE

↓

LONG-TERM OUTCOME.

Include:

  • meningitis;
  • encephalitis;
  • neonatal systemic disease;
  • paralysis;
  • rash;
  • myocarditis;
  • gastrointestinal disease;
  • long-term neurological sequelae.

6. COXSACKIE A7

Reconstruct historical A7-associated paralytic disease.

Investigate:

  • spinal-grey-matter tropism;
  • anterior-horn injury;
  • motor-neuron injury;
  • ventral roots;
  • residual paresis;
  • denervation;
  • genotype;
  • receptor biology;
  • host susceptibility.

Build modern cellular and animal models where justified.

7. BROAD NON-POLIO ENTEROVIRUS PARALYSIS PROGRAMME

Include relevant:

  • CV-A7;
  • CV-A9;
  • CV-B viruses;
  • Echoviruses;
  • EV-A71;
  • EV-D68;
  • EV-70;
  • emerging neurotropic non-polio enteroviruses.

Determine type-specific:

  • neuroinvasion;
  • spinal tropism;
  • motor-neuron injury;
  • brainstem involvement;
  • paralysis severity;
  • long-term disability.

Do not assume every serotype has equal paralytic potential.

8. EV-A71

Establish the complete EV-A71 continuum:

HAND, FOOT AND MOUTH DISEASE

↓

MENINGITIS

↓

BRAINSTEM ENCEPHALITIS

↓

RHOMBENCEPHALITIS

↓

ENCEPHALOMYELITIS

↓

ACUTE FLACCID PARALYSIS

↓

AUTONOMIC INSTABILITY

↓

NEUROGENIC PULMONARY OEDEMA

↓

CARDIOPULMONARY COLLAPSE.

Study:

  • genotype;
  • antigenic evolution;
  • receptor biology;
  • neurovirulence;
  • brainstem tropism;
  • spinal tropism;
  • motor-neuron injury;
  • autonomic injury;
  • neurogenic pulmonary oedema;
  • long-term neurological outcomes;
  • motor disability;
  • auditory/vestibular abnormalities.

9. EV-A71 ASIA-PACIFIC EPIDEMIC PROGRAMME

Study epidemics in:

  • Taiwan;
  • Malaysia;
  • Singapore;
  • China;
  • Vietnam;
  • Cambodia;
  • Japan;
  • South Korea;
  • Australia;
  • other affected regions.

Research:

  • epidemic waves;
  • genotype changes;
  • age-related susceptibility;
  • host genetics;
  • immune response;
  • neurological severity;
  • brainstem imaging;
  • cardiopulmonary collapse;
  • mortality;
  • disability;
  • vaccine effects.

10. EV-D68 AND ACUTE FLACCID MYELITIS

Study:

RESPIRATORY INFECTION

↓

NEUROLOGICAL PRODROME

↓

SPINAL GREY-MATTER INJURY

↓

ANTERIOR-HORN DAMAGE

↓

MOTOR-NEURON LOSS

↓

ASYMMETRIC FLACCID WEAKNESS

↓

DENERVATION

↓

PERSISTENT MOTOR DISABILITY.

Use:

  • respiratory PCR;
  • stool testing;
  • CSF immune studies;
  • spinal MRI;
  • EMG;
  • NCS;
  • CMAP;
  • motor-unit-number estimation;
  • quantitative strength;
  • muscle imaging;
  • long-term motor follow-up.

PART IV — ENTRY SITES AND CELLULAR/TISSUE TROPISM

11. OROPHARYNGEAL COMPARTMENT

Investigate:

  • throat;
  • tonsillar tissue;
  • oral mucosa;
  • salivary compartments;
  • pharyngeal epithelium.

Study:

  • early viral replication;
  • shedding;
  • serotype;
  • lymphoid interaction;
  • relationship to later systemic or neurological disease.

12. GASTROINTESTINAL ENTRY / PERSISTENCE COMPARTMENT

Map:

  • stomach;
  • duodenum;
  • jejunum;
  • terminal ileum;
  • Peyer’s patches;
  • intestinal epithelium;
  • enteric nervous system;
  • gut-associated lymphoid tissue.

13. EPITHELIAL CELLS

Map EV interactions with:

  • oropharyngeal epithelium;
  • respiratory epithelium;
  • gastric epithelium;
  • intestinal epithelium;
  • pancreatic tissue;
  • thyroid epithelium;
  • skin-associated epithelial structures.

Central question:

WHICH EV → WHICH EPITHELIAL CELL → WHICH ORGAN → WHICH IMMUNE RESPONSE → WHICH LONG-TERM CONSEQUENCE?

14. ENDOTHELIAL CELLS

Study:

  • cerebral endothelium;
  • BBB;
  • blood-spinal-cord barrier;
  • myocardial microvasculature;
  • skeletal-muscle microvasculature;
  • pancreatic microvasculature;
  • vasa nervorum;
  • systemic vascular endothelium.

Measure:

  • endothelial activation;
  • leukocyte adhesion;
  • permeability;
  • complement;
  • capillary flow;
  • tissue oxygenation;
  • vascular inflammation.

15. FIBROBLASTS

Investigate:

  • susceptibility to infection;
  • inflammatory signalling;
  • extracellular-matrix changes;
  • scar formation;
  • fibrosis;
  • chronic tissue remodelling.

Particular relevance:

  • myocardium;
  • skeletal muscle;
  • vascular tissues;
  • inflammatory connective-tissue processes.

16. LEUKOCYTES

Study:

  • monocytes;
  • macrophages;
  • B cells;
  • T cells;
  • dendritic cells.

Determine whether these cells participate in:

  • viral dissemination;
  • viral carriage;
  • persistent antigen;
  • altered immune activation;
  • chronic inflammation.

PART V — RESPIRATORY DISEASE

17. RHINOSINUSITIS

Study EV-positive upper-airway disease separately from:

  • bacterial sinusitis;
  • allergic rhinitis;
  • noninfectious chronic sinusitis.

Investigate:

  • serotype;
  • viral load;
  • epithelial infection;
  • persistence;
  • relationship to neurological disease.

18. PHARYNGITIS

Study:

  • throat pain;
  • tonsillar involvement;
  • oropharyngeal shedding;
  • early viral load;
  • type-specific disease.

The throat should be treated as an important early diagnostic specimen, particularly when neurological illness follows an acute upper-airway prodrome.

19. BRONCHITIS

Investigate:

  • bronchial epithelial infection;
  • inflammatory response;
  • cough;
  • wheeze;
  • lower respiratory progression;
  • later neurological disease.

20. BRONCHIOLITIS

Prioritise:

  • infants;
  • children;
  • EV-D68;
  • severe respiratory disease.

Measure:

  • oxygenation;
  • respiratory support;
  • coinfections;
  • viral load;
  • neurological follow-up.

21. PLEURISY

Differentiate:

  • pleural inflammation;
  • pleurodynia;
  • intercostal myositis;
  • pericarditis;
  • pneumonia.

22. PNEUMONIA

Create adult, paediatric and neonatal enterovirus pneumonia programmes.

Differentiate:

  • direct viral pneumonia;
  • secondary bacterial pneumonia;
  • aspiration pneumonia;
  • cardiogenic pulmonary oedema;
  • neurogenic pulmonary oedema;
  • mixed pulmonary disease.

Do not assume that pneumonia is enteroviral solely because an enterovirus is found elsewhere.

PART VI — HAND, FOOT AND MOUTH / ORAL / SKIN / EYE

23. HAND, FOOT AND MOUTH DISEASE

Study:

  • EV-A71;
  • CV-A16;
  • CV-A6;
  • other associated serotypes.

Map:

ORAL / CUTANEOUS DISEASE

↓

SYSTEMIC ILLNESS

↓

NEUROLOGICAL WARNING SIGNS

↓

BRAINSTEM DISEASE

↓

AUTONOMIC / CARDIOPULMONARY COMPLICATIONS.

Develop parent and clinician education about neurological red flags.

24. HERPANGINA

Characterise:

  • vesicular or ulcerative pharyngeal lesions;
  • fever;
  • serotype;
  • shedding;
  • systemic manifestations.

25. ENANTHEM / TONGUE / MOUTH ULCERS

Map:

  • oral mucosal lesions;
  • tongue lesions;
  • pharyngeal lesions;
  • serotype-specific morphology;
  • mucosal immune response.

26. SKIN MANIFESTATIONS

Study:

  • vesicles;
  • maculopapular rash;
  • petechiae;
  • urticaria;
  • vasculitic lesions.

Where clinically justified, biopsy should distinguish:

  • viral skin involvement;
  • immune-mediated vasculitis;
  • allergic or nonspecific cutaneous reactions.

27. HAEMORRHAGIC CONJUNCTIVITIS

Maintain enterovirus surveillance for:

  • outbreak identification;
  • viral typing;
  • ocular shedding;
  • neurological/systemic complications.

PART VII — RAPID ACUTE ENTEROVIRUS DIAGNOSTICS

28. SAME-DAY MULTI-COMPARTMENT SAMPLING

This should be an explicit high-priority diagnostic workstream rather than being buried within general virology.

In suspected acute enterovirus neurological or systemic disease, collect clinically appropriate specimens as early as possible:

  • CSF;
  • stool;
  • throat swab;
  • nasopharyngeal swab;
  • oropharyngeal swab;
  • lower respiratory specimen;
  • serum;
  • plasma;
  • whole blood;
  • PBMCs.

Timing should be recorded precisely.

DO NOT WAIT UNTIL THE VIRUS IS HARDER TO DETECT.

The programme should determine, by serotype and clinical syndrome:

  • which specimen is most sensitive;
  • on which illness day;
  • how sensitivity falls with time;
  • whether multi-site sampling materially improves diagnosis.

29. RAPID PAN-ENTEROVIRUS TEST

Develop a genuine urgent-diagnostics pathway:

SAMPLE RECEIVED

↓

PAN-ENTEROVIRUS RESULT

↓

SPECIES

↓

SEROTYPE

↓

SEQUENCE

↓

ACTIONABLE CLINICAL RESULT.

Technologies to develop and compare:

  • conventional real-time RT-PCR;
  • multiplex RT-PCR;
  • cartridge-based RT-PCR;
  • digital PCR;
  • droplet digital PCR;
  • isothermal amplification;
  • CRISPR-based detection;
  • rapid antigen/protein detection;
  • nanopore sequencing;
  • other portable sequencing platforms.

Endpoints should include:

  • analytical sensitivity;
  • clinical sensitivity;
  • specificity;
  • time to result;
  • type coverage;
  • cost;
  • point-of-care feasibility.

30. RAPID SEROTYPING

A positive result reading only:

“ENTEROVIRUS DETECTED”

is less informative than:

“ENTEROVIRUS B — COXSACKIE B3”

or

“ENTEROVIRUS A — EV-A71.”

Develop:

  • rapid VP1 sequencing;
  • targeted amplicon sequencing;
  • portable nanopore sequencing;
  • targeted capture;
  • rapid WGS where feasible.

The research objective is:

POSITIVE EV TEST → TYPE IN HOURS RATHER THAN DAYS OR WEEKS.

31. RAPID VIRAL-LOAD QUANTIFICATION

Develop validated quantitative assays capable of monitoring:

  • baseline viral burden;
  • acute viral kinetics;
  • antiviral response;
  • virological suppression;
  • rebound;
  • resistance-associated breakthrough.

Where blood is not the primary viral compartment, develop specimen-specific quantitative approaches.

32. NATIONAL / INTERNATIONAL ENTEROVIRUS REFERENCE-LABORATORY NETWORK

Provide:

  • pan-EV PCR;
  • species-specific assays;
  • type-specific assays;
  • qPCR;
  • ddPCR;
  • VP1;
  • whole-genome sequencing;
  • metagenomics;
  • enrichment/capture sequencing;
  • culture;
  • neutralisation assays;
  • acute/convalescent serology;
  • CSF antibody studies;
  • validated strand-specific RNA assays;
  • in-situ hybridisation;
  • viral-protein detection;
  • defective-genome analysis;
  • resistance testing.

PART VIII — RAPID BLOOD TEST FOR PERSISTENT ENTEROVIRUS

33. DEDICATED RAPID PERSISTENT-ENTEROVIRUS BLOOD-TEST PROGRAMME

This is separate from acute PCR testing.

The goal should be development of a practical rapid blood-based test capable of detecting persistent or low-level infection when conventional acute-phase testing has become insensitive.

Research:

  • ultrasensitive qPCR;
  • ddPCR;
  • PBMC-associated EV RNA;
  • viral RNA enrichment;
  • capsid/viral protein detection;
  • circulating viral antigen;
  • extracellular-vesicle-associated viral material;
  • immune-complex-associated antigen;
  • EV-specific neutralising antibody patterns;
  • EV-specific B-cell responses;
  • EV-specific T-cell responses;
  • host transcriptional signatures;
  • combined multi-analyte classifiers.

34. RAPID BLOOD TEST — DEVELOPMENT TARGET

The eventual pathway should aim for:

BLOOD DRAW

↓

ULTRASENSITIVE EV RNA / ANTIGEN / IMMUNE-SIGNATURE PANEL

↓

POSITIVE / NEGATIVE / INDETERMINATE

↓

SPECIES / SEROTYPE IF POSSIBLE

↓

QUANTIFY

↓

SEQUENCE

↓

TARGETED TISSUE INVESTIGATION IF NECESSARY.

The blood test should be validated against tissue-positive and tissue-negative cohorts rather than simply against symptoms.

35. DISTINGUISH PERSISTENT VIRUS FROM PAST EXPOSURE

A chronic blood assay should distinguish:

  • remote antibody evidence;
  • recent infection;
  • active viraemia;
  • cell-associated RNA;
  • persistent antigen;
  • low-level ongoing replication;
  • immunological memory without current infection.

PART IX — PERSISTENT ENTEROVIRUS TISSUE DIAGNOSTICS

36. BIOPSY-BASED PERSISTENCE DIAGNOSTICS

Build on previous GI enterovirus persistence approaches while improving:

  • specificity;
  • reproducibility;
  • molecular confirmation;
  • serotyping;
  • anatomical localisation.

Potential tissues, where clinically justified or independently obtained:

  • stomach;
  • duodenum;
  • terminal ileum;
  • Peyer’s patches;
  • skeletal muscle;
  • myocardium;
  • peripheral nerve;
  • lymphoid tissue;
  • other affected organs.

Do not rely on a single VP1 immunostain.

Where possible require:

RNA

PROTEIN

CELLULAR LOCALISATION

SEQUENCE

REPLICATION-ASSOCIATED EVIDENCE.

37. CHRONIC SEROTYPING

Develop:

  • highly sensitive VP1;
  • digital amplification;
  • capture/enrichment;
  • WGS;
  • single-cell methods;
  • spatial sequencing;
  • mixed-infection detection;
  • defective-genome analysis.

Goal:

PERSISTENT EV → SPECIES → TYPE → GENOME → RESISTANCE PROFILE → TREATMENT.

38. VIRAL RESERVOIR MAPPING

Investigate possible reservoirs in:

  • brain;
  • brainstem;
  • spinal cord;
  • anterior horn;
  • dorsal-root ganglia;
  • autonomic ganglia;
  • peripheral nerves;
  • enteric nervous system;
  • stomach;
  • small intestine;
  • terminal ileum;
  • Peyer’s patches;
  • lymphoid tissue;
  • skeletal muscle;
  • myocardium;
  • pancreas;
  • vascular tissue;
  • immune cells.

PART X — COMPLETE CNS NEUROPATHOLOGY

39. COMPLETE CNS ANATOMICAL MAPPING

Map:

  • meninges;
  • frontal cortex;
  • motor cortex;
  • sensory cortex;
  • temporal cortex;
  • parietal cortex;
  • occipital cortex;
  • limbic system;
  • hippocampus;
  • amygdala;
  • thalamus;
  • hypothalamus;
  • basal ganglia;
  • cerebellum;
  • midbrain;
  • pons;
  • medulla;
  • spinal cord;
  • anterior horns.

Use:

  • MRI;
  • advanced MRI;
  • neuropathology;
  • viral localisation;
  • immune profiling;
  • spatial transcriptomics.

40. BRAINSTEM DISEASE

Investigate:

  • cranial motor nuclei;
  • autonomic nuclei;
  • respiratory centres;
  • swallowing circuitry;
  • ocular-motor systems;
  • auditory/vestibular systems;
  • cardiovascular control.

Correlate:

  • MRI;
  • autonomic tests;
  • swallowing studies;
  • audiovestibular testing;
  • neurological examination.

PART XI — MOTOR / ANTERIOR-HORN / POLIO-LIKE DISEASE

41. POLIOMYELITIS-LIKE PHENOTYPE

Define:

  • acute flaccid weakness;
  • asymmetric weakness;
  • segmental weakness;
  • reduced or absent reflexes;
  • muscle wasting;
  • fasciculations;
  • bulbar weakness;
  • respiratory weakness;
  • bladder/bowel neurological dysfunction;
  • persistent paresis.

42. LEG PARESIS

Study:

  • unilateral paresis;
  • bilateral paresis;
  • asymmetric paresis;
  • proximal weakness;
  • distal weakness.

Differentiate:

  • anterior-horn disease;
  • corticospinal injury;
  • radiculopathy;
  • peripheral motor neuropathy;
  • neuromuscular-junction disease;
  • myositis.

Use:

  • spinal MRI;
  • EMG;
  • NCS;
  • CMAP;
  • MUNE;
  • quantitative strength.

43. MUSCLE ATROPHY / WASTING

Determine whether wasting is caused by:

  • denervation;
  • motor-neuron loss;
  • motor-root injury;
  • peripheral neuropathy;
  • primary muscle disease;
  • malnutrition;
  • prolonged immobility;
  • mixed mechanisms.

Measure:

  • MRI muscle cross-sectional area;
  • muscle ultrasound;
  • dynamometry;
  • EMG;
  • CMAP;
  • motor-unit-number estimation;
  • reinnervation.

44. FASCICULATIONS

Investigate whether fasciculations reflect:

  • anterior-horn injury;
  • lower-motor-neuron injury;
  • peripheral motor-axon injury;
  • collateral reinnervation;
  • peripheral motor hyperexcitability.

Track longitudinally with EMG.

45. MUSCLE SPASMS

Differentiate:

  • painful muscle spasm;
  • dystonic movement;
  • spasticity;
  • peripheral-nerve hyperexcitability;
  • electrolyte/metabolic causes;
  • central motor phenomena.

46. MYOCLONUS

Localise:

  • cortical myoclonus;
  • subcortical myoclonus;
  • brainstem myoclonus;
  • spinal myoclonus.

Include EV-A71-associated myoclonic phenomena in surveillance.

Use neurophysiological localisation where feasible.

PART XII — RADICULITIS / CERVICAL ROOTS / BRACHIAL PLEXUS

47. RADICULITIS

Investigate inflammatory or infectious disease affecting spinal nerve roots.

Possible manifestations:

  • radicular pain;
  • motor weakness;
  • sensory loss;
  • reflex abnormalities.

Use:

  • spinal MRI;
  • nerve-root imaging;
  • contrast enhancement where appropriate;
  • CSF;
  • EMG;
  • NCS;
  • F-waves;
  • H-reflexes;
  • virology;
  • immune studies.

Differentiate from:

  • anterior-horn disease;
  • GBS;
  • plexopathy;
  • peripheral neuropathy.

48. BRACHIAL-PLEXUS / CERVICAL MOTOR PROGRAMME

Map the complete anatomical chain:

CERVICAL SPINAL CORD

↓

ANTERIOR HORN

↓

VENTRAL ROOT

↓

CERVICAL ROOTS

↓

BRACHIAL PLEXUS

↓

PERIPHERAL MOTOR NERVES

↓

SHOULDER / ARM / FOREARM / HAND MUSCLE.

Particularly investigate upper-limb-predominant weakness in AFM and other enteroviral motor syndromes.

49. TRUE BRACHIAL PLEXOPATHY VS CENTRAL MOTOR DISEASE

Differentiate:

  • cervical anterior-horn injury;
  • cervical myelitis;
  • radiculitis;
  • brachial neuritis;
  • true plexopathy;
  • peripheral motor neuropathy;
  • primary muscle disease.

Use:

  • cervical MRI;
  • brachial-plexus MRI;
  • MR neurography;
  • EMG;
  • NCS;
  • SNAPs;
  • CMAPs;
  • F-waves;
  • motor-unit analysis.

PART XIII — GBS / MILLER FISHER / IMMUNE NEUROPATHY

50. GUILLAIN–BARRÉ SYNDROME

Investigate GBS after laboratory-defined enterovirus infection.

Characterise:

  • demyelinating phenotype;
  • axonal phenotype;
  • motor predominance;
  • sensory abnormalities;
  • cranial neuropathies;
  • respiratory involvement;
  • autonomic instability.

Measure:

  • CSF;
  • NCS;
  • EMG;
  • ganglioside antibodies;
  • acute virology;
  • timing from infection.

51. MILLER FISHER SYNDROME

Create a dedicated MFS / anti-GQ1b-spectrum programme.

Characterise:

  • ophthalmoplegia;
  • ataxia;
  • areflexia;
  • facial weakness;
  • bulbar symptoms;
  • sensory abnormalities.

Measure:

  • anti-GQ1b;
  • anti-GT1a;
  • other ganglioside antibodies;
  • CSF;
  • NCS/EMG;
  • acute EV PCR where appropriate.

Differentiate:

MILLER FISHER SYNDROME

from

EV BRAINSTEM ENCEPHALITIS

from

RHOMBENCEPHALITIS

from

CRANIAL NEUROPATHY

from

AFM.

PART XIV — PERIPHERAL NEUROPATHY

52. SMALL-FIBRE NEUROPATHY

Study:

  • burning pain;
  • cutaneous pain;
  • mechanical allodynia;
  • thermal allodynia;
  • hyperalgesia;
  • paresthesia;
  • dysesthesia;
  • abnormal sweating;
  • vasomotor abnormalities;
  • temperature dysregulation;
  • orthostatic symptoms;
  • GI autonomic symptoms;
  • bladder autonomic symptoms.

Use:

  • intraepidermal nerve-fibre density;
  • sweat-gland nerve-fibre density;
  • quantitative sensory testing;
  • thermal testing;
  • sudomotor testing;
  • formal autonomic testing;
  • corneal confocal microscopy where validated.

53. LARGE-FIBRE NEUROPATHY

Study:

  • vibration loss;
  • proprioceptive loss;
  • sensory ataxia;
  • reflex abnormalities;
  • weakness;
  • conduction abnormalities.

Use:

  • NCS;
  • EMG;
  • SNAP;
  • CMAP;
  • F-waves;
  • H-reflexes;
  • quantitative strength;
  • nerve ultrasound;
  • MR neurography.

54. MIXED SMALL / LARGE / AUTONOMIC NEUROPATHY

Create integrated phenotyping:

SKIN BIOPSY + NCS/EMG + AUTONOMIC TESTING + QST + VASCULAR TESTING + VIROLOGY + IMMUNOLOGY.

PART XV — COMPLEX REGIONAL PAIN SYNDROME / PAIN

55. COMPLEX REGIONAL PAIN SYNDROME

Investigate CRPS-like disease after objectively defined neurological infection or nerve injury.

Study:

  • small-fibre pathology;
  • autonomic dysfunction;
  • neurogenic inflammation;
  • altered limb temperature;
  • colour changes;
  • oedema;
  • microvascular dysfunction;
  • central sensitisation;
  • immobilisation effects.

Do not assume that ordinary CRPS is generally caused by enterovirus.

56. NEUROPATHIC PAIN

Treat and research:

  • burning pain;
  • mechanical allodynia;
  • thermal allodynia;
  • electric pain;
  • hyperalgesia;
  • paresthesia;
  • dysesthesia.

Continue disease-modifying research while providing symptomatic treatment.

PART XVI — SENSORY / AUDIOVESTIBULAR / MIGRAINE

57. PHOTOPHOBIA

Investigate:

  • retinal input;
  • optic pathways;
  • thalamic pathways;
  • trigeminal pathways;
  • brainstem sensory gating;
  • cortical sensory processing.

Differentiate:

  • meningitic photophobia;
  • encephalitic photophobia;
  • migraine-related photophobia.

58. HYPERACUSIS

Study:

  • cochlear function;
  • VIII-nerve function;
  • auditory brainstem pathways;
  • central auditory gain;
  • sensory gating.

59. TINNITUS

Investigate:

  • cochlear injury;
  • auditory nerve;
  • brainstem auditory nuclei;
  • central auditory pathways.

Use:

  • audiometry;
  • otoacoustic emissions;
  • auditory brainstem responses;
  • vestibular testing.

60. LABYRINTHITIS / INNER-EAR DISEASE

Study:

  • labyrinthitis;
  • vestibular neuritis-like illness;
  • sensorineural hearing loss;
  • vertigo;
  • disequilibrium;
  • tinnitus.

Differentiate:

  • labyrinth disease;
  • VIII-nerve disease;
  • brainstem nuclei involvement;
  • central vestibular disease.

61. EPIDEMIC VERTIGO / DEAFNESS

Revisit historical epidemic reports and build prospective surveillance for modern laboratory-defined enterovirus cases.

62. MIGRAINE

Investigate whether a biologically defined post-enteroviral subgroup develops migraine through:

  • trigeminovascular activation;
  • brainstem sensory processing;
  • autonomic dysfunction;
  • endothelial/vascular instability;
  • cerebral-perfusion changes;
  • neuroinflammatory signalling.

Do not classify ordinary migraine as enteroviral without evidence.

PART XVII — DIRECT OBJECTIVE BLOOD-VOLUME TESTING

63. LOW CIRCULATING BLOOD VOLUME — OBJECTIVE MEASUREMENT

This programme must remain separate from cerebral-perfusion imaging.

The question is:

DOES THE PATIENT ACTUALLY HAVE REDUCED CIRCULATING BLOOD VOLUME?

Measure directly where validated testing is available:

  • total circulating blood volume;
  • plasma volume;
  • red-cell volume;
  • percentage deviation from predicted blood volume.

Do not diagnose hypovolaemia merely from:

  • tachycardia;
  • dizziness;
  • orthostatic symptoms;
  • low BP;
  • cerebral hypoperfusion.

64. BLOOD-VOLUME PHYSIOLOGY

Investigate why objectively confirmed low blood volume occurs.

Potential mechanisms:

  • renal sodium loss;
  • impaired RAAS response;
  • autonomic neuropathy;
  • excessive venous capacitance;
  • peripheral pooling;
  • endothelial dysfunction;
  • altered thirst/fluid regulation;
  • reduced red-cell volume;
  • plasma-volume loss;
  • cardiac filling abnormalities.

65. BLOOD-VOLUME + AUTONOMIC TESTING

Combine blood-volume measurement with:

  • supine BP/HR;
  • active stand;
  • tilt-table testing;
  • beat-to-beat BP;
  • venous-pooling studies;
  • echocardiographic filling measurements;
  • renin;
  • aldosterone;
  • renal function;
  • electrolytes;
  • urinary sodium where useful.

66. LOW-BLOOD-VOLUME TREATMENT

Test biology-directed interventions.

Potential research interventions:

  • oral fluid optimisation;
  • oral rehydration solutions;
  • sodium supplementation where medically appropriate;
  • compression stockings;
  • abdominal compression;
  • venous-pooling treatment;
  • vasoconstrictors in selected patients;
  • volume-regulating pharmacology;
  • carefully selected IV fluid strategies.

Do not assume chronic IV saline is universally safe or appropriate.

Endpoints:

  • direct blood-volume measurement;
  • orthostatic haemodynamics;
  • cardiac filling;
  • cerebral blood flow;
  • renal/electrolyte safety;
  • neurological function;
  • functional tolerance.

PART XVIII — CEREBRAL HYPOPERFUSION / SEGAMI OASIS / NEUROGAM

67. SEGAMI OASIS / NEUROGAM QUANTITATIVE BRAIN-PERFUSION SPECT

Create a dedicated quantitative cerebral-perfusion research programme using brain-perfusion SPECT and appropriately validated analysis platforms such as Segami Oasis / NeuroGam.

This workstream must not be described as a direct blood-volume test.

Instead it asks:

IS CEREBRAL PERFUSION ABNORMAL?

Map where technically interpretable:

  • frontal cortex;
  • motor cortex;
  • sensory cortex;
  • temporal cortex;
  • parietal cortex;
  • occipital cortex;
  • limbic regions;
  • thalamus;
  • basal ganglia;
  • cerebellum;
  • brainstem where resolution permits.

68. QUANTITATIVE CEREBRAL BLOOD-FLOW PROGRAMME

Combine SPECT with:

  • ASL-MRI;
  • dynamic perfusion MRI;
  • transcranial Doppler;
  • orthostatic cerebral-flow measurement;
  • PET perfusion/metabolic approaches where scientifically justified;
  • other validated cerebral-flow techniques.

Study:

  • resting perfusion;
  • regional hypoperfusion;
  • hyperperfusion;
  • hemispheric asymmetry;
  • cortical/subcortical patterns;
  • orthostatic changes;
  • longitudinal change.

69. BLOOD VOLUME AND CEREBRAL PERFUSION — LINKED BUT SEPARATE

The programme should explicitly test:

DIRECT BLOOD-VOLUME MEASUREMENT

AUTONOMIC / HAEMODYNAMIC TESTING

SEGAMI OASIS / NEUROGAM BRAIN-PERFUSION SPECT

ASL-MRI / OTHER CEREBRAL-FLOW MEASURES

=

AN INTEGRATED BLOOD-VOLUME / AUTONOMIC / PERFUSION PHENOTYPE.

Do not infer low total blood volume from SPECT alone.

Do not infer cerebral hypoperfusion simply from low blood volume without actually measuring cerebral flow.

70. LONGITUDINAL PERFUSION

Follow:

ACUTE DISEASE

↓

EARLY RECOVERY

↓

PERSISTENT NEUROLOGICAL DISEASE

↓

TREATMENT

↓

REHABILITATION.

Determine whether perfusion:

  • normalises;
  • persists;
  • fluctuates;
  • correlates with blood volume;
  • correlates with dysautonomia;
  • correlates with endothelial disease;
  • correlates with neuroinflammation;
  • changes after successful treatment.

PART XIX — DYSAUTONOMIA

71. NATIONAL DYSAUTONOMIA RESEARCH PROGRAMME

Map:

  • hypothalamus;
  • brainstem autonomic nuclei;
  • nucleus tractus solitarius-related networks;
  • spinal autonomic pathways;
  • sympathetic ganglia;
  • parasympathetic pathways;
  • cardiac autonomic nerves;
  • sudomotor fibres;
  • vasomotor fibres;
  • enteric nerves;
  • bladder pathways.

Differentiate:

  • central dysautonomia;
  • autonomic SFN;
  • autonomic ganglionopathy;
  • vascular dysfunction;
  • autoimmune autonomic disease;
  • persistent infection;
  • mixed mechanisms.

72. EXPANSION OF DYSAUTONOMIA SPECIALISTS / LABORATORIES

Develop:

  • autonomic neurologists;
  • autonomic specialists;
  • autonomic nurses;
  • autonomic physiologists;
  • regional autonomic labs;
  • paediatric autonomic centres;
  • tertiary referral centres.

Testing should include:

  • active stand;
  • tilt;
  • beat-to-beat BP;
  • HRV;
  • Valsalva;
  • cardiovagal testing;
  • sudomotor tests;
  • ambulatory haemodynamics;
  • cerebral-flow measurement where appropriate.

73. AUTONOMIC-NERVE REPAIR

Research recovery of:

  • sympathetic nerves;
  • parasympathetic nerves;
  • sudomotor fibres;
  • vasomotor fibres;
  • cardiac autonomic nerves;
  • enteric autonomic pathways;
  • bladder pathways.

PART XX — RAYNAUD’S / VASCULAR / ENDOTHELIAL

74. RAYNAUD’S PHENOMENON

Investigate:

  • digital vasospasm;
  • cold-triggered vascular responses;
  • sympathetic hyperactivity;
  • endothelial dysfunction;
  • microvascular abnormalities;
  • small-fibre neuropathy;
  • connective-tissue autoimmunity.

Differentiate:

PRIMARY RAYNAUD’S

from

SECONDARY RAYNAUD’S.

75. PERIVASCULAR CUFFING

Where demonstrated pathologically, map:

  • lymphocytic or mononuclear cuffs;
  • endothelial activation;
  • leukocyte trafficking;
  • complement;
  • vascular permeability;
  • nearby neuronal injury.

Map in:

  • CNS;
  • spinal cord;
  • DRG;
  • peripheral nerves.

76. VASCULAR / ENDOTHELIAL INFLAMMATION

Study:

  • BBB;
  • blood-spinal-cord barrier;
  • endothelial activation;
  • pericytes;
  • capillary dysfunction;
  • systemic endothelium;
  • myocardial microvasculature;
  • vasa nervorum.

77. VASCULAR-INFLAMMATION TREATMENT

Research:

  • antivirals where persistence exists;
  • endothelial protection;
  • barrier stabilisation;
  • leukocyte-trafficking modulation;
  • cytokine/chemokine interventions;
  • complement inhibition where appropriate;
  • pericyte support;
  • microvascular restoration;
  • vasa-nervorum repair.

PART XXI — GI / ENTERIC DISEASE

78. VOMITING AND DIARRHOEA

Characterise acute enteroviral GI syndromes with:

  • stool viral testing;
  • serotyping;
  • hydration;
  • electrolyte testing;
  • inflammatory markers;
  • neurological follow-up.

79. GASTRITIS

Investigate:

  • acute mucosal inflammation;
  • chronic/persistent viral material;
  • gastric immune activation;
  • dyspepsia;
  • gastric neuropathic/autonomic effects.

80. TERMINAL ILEITIS

Study:

  • terminal-ileal inflammation;
  • Peyer’s patches;
  • viral RNA/protein;
  • mesenteric lymph nodes;
  • Crohn’s differential.

81. COLITIS

Distinguish:

  • direct infectious colitis;
  • post-infectious inflammation;
  • IBD;
  • unrelated inflammatory colitis.

82. MESENTERIC ADENITIS

Create a dedicated mesenteric-lymph-node workstream.

Study:

  • abdominal pain;
  • mesenteric lymph-node enlargement;
  • terminal ileal inflammation;
  • stool enterovirus;
  • systemic virology;
  • lymphoid immune activation.

Differentiate:

  • appendicitis;
  • Crohn’s disease;
  • bacterial adenitis;
  • lymphoma;
  • other lymphadenopathy.

83. HEPATITIS

Particularly investigate:

  • neonatal enterovirus;
  • systemic severe infection;
  • immunocompromised disease.

Measure:

  • AST;
  • ALT;
  • bilirubin;
  • INR;
  • coagulation;
  • viral load.

84. GERD

Investigate whether post-enteroviral reflux symptoms reflect:

  • vagal dysfunction;
  • oesophageal dysmotility;
  • delayed gastric emptying;
  • autonomic neuropathy;
  • ordinary reflux disease.

85. FUNCTIONAL DYSPEPSIA

Do not allow the syndrome label to end investigation.

Study:

  • gastric accommodation;
  • gastric emptying;
  • vagal function;
  • mucosal inflammation;
  • autonomic dysfunction;
  • visceral sensory pathways.

PART XXII — NEUROGASTROENTEROLOGY / GI PARESIS

86. GASTROPARESIS

Investigate:

  • vagal neuropathy;
  • enteric neuropathy;
  • autonomic injury;
  • smooth-muscle dysfunction;
  • brainstem autonomic dysfunction.

Use validated gastric-emptying assessment.

87. PARALYTIC ILEUS

Explicitly investigate:

PARALYTIC ILEUS.

Potential mechanisms:

  • brainstem autonomic injury;
  • spinal autonomic injury;
  • autonomic ganglionopathy;
  • enteric nervous-system injury;
  • small-fibre/autonomic neuropathy;
  • smooth-muscle dysfunction;
  • systemic inflammation;
  • metabolic/electrolyte disturbance;
  • medications;
  • mixed disease.

Differentiate:

  • paralytic ileus;
  • mechanical obstruction;
  • chronic intestinal pseudo-obstruction;
  • gastroparesis;
  • slow-transit dysmotility.

88. CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Investigate:

  • enteric neuronal disease;
  • smooth-muscle disease;
  • autonomic neuropathy;
  • immune-mediated enteric disease;
  • possible persistent infection.

89. NEUROGENIC BOWEL / GI PARESIS

Study:

  • oesophageal dysmotility;
  • gastroparesis;
  • intestinal dysmotility;
  • impaired colonic propulsion;
  • slow transit;
  • neurogenic constipation;
  • severe enteral intolerance.

Use:

  • gastric-emptying testing;
  • transit studies;
  • manometry;
  • autonomic testing;
  • enteric neuromuscular investigation.

PART XXIII — NUTRITION / ENTERAL FEEDING / TPN

90. POST-ENTEROVIRAL CNS NUTRITION PROGRAMME

Recognise that CNS, brainstem, bulbar, autonomic and enteric disease can impair the ability to eat safely or obtain sufficient nutrition.

Central principle:

INABILITY TO EAT SAFELY DOES NOT MEAN INABILITY TO RECEIVE NUTRITION.

91. SWALLOWING / BULBAR ASSESSMENT

Provide:

  • speech and language therapy;
  • FEES;
  • videofluoroscopic swallow study;
  • aspiration assessment;
  • cough-effectiveness testing;
  • respiratory assessment;
  • dietetic review.

Recognise silent aspiration.

92. NG FEEDING

Research appropriate use when gastric feeding is feasible.

Assess:

  • placement;
  • aspiration risk;
  • gastric intolerance;
  • duration;
  • tube displacement;
  • nutritional adequacy.

93. NJ FEEDING

Assess post-pyloric feeding particularly where there is:

  • severe gastroparesis;
  • gastric feeding intolerance;
  • severe reflux;
  • recurrent aspiration;
  • upper-GI dysfunction.

Failure of gastric feeding does not automatically equal failure of enteral nutrition.

94. PEG / RIG

Develop expertise in longer-term gastric feeding.

Monitor:

  • infection;
  • leakage;
  • aspiration;
  • tube dysfunction;
  • buried bumper;
  • nutritional outcomes.

95. GJ / PEG-J

Use when gastric access is useful but jejunal feeding is physiologically preferable.

96. DIRECT JEJUNOSTOMY

Study selected use in persistent severe upper-GI dysfunction where direct jejunal feeding is appropriate.

97. PARENTERAL NUTRITION / TPN

Keep completely separate from tube feeding.

NG / NJ / PEG / RIG / GJ / PEG-J / JEJUNOSTOMY = ENTERAL NUTRITION.

TPN = PARENTERAL / INTRAVENOUS NUTRITION.

Where the GI tract cannot safely or effectively provide adequate nutrition, refer to specialist intestinal-failure/nutrition-support services.

Monitor:

  • catheter bloodstream infection;
  • thrombosis;
  • glucose;
  • electrolytes;
  • fluid balance;
  • liver function;
  • triglycerides;
  • vitamins;
  • trace elements;
  • refeeding syndrome;
  • long-term line complications.

PART XXIV — MUSCLE DISEASE

98. ACUTE ENTEROVIRAL MYOSITIS

Study:

  • severe myalgia;
  • weakness;
  • CK;
  • MRI muscle;
  • muscle ultrasound;
  • EMG;
  • viral RNA/protein;
  • biopsy where clinically appropriate.

99. INFECTIOUS MYOSITIS MIMICKING POLYMYOSITIS

Differentiate:

  • direct infectious myositis;
  • inflammatory-myopathy mimic;
  • true autoimmune inflammatory myopathy.

Use:

  • CK;
  • MRI;
  • EMG;
  • histology;
  • virology;
  • myositis antibody panels.

100. COXSACKIEVIRUS / DERMATOMYOSITIS / POLYMYOSITIS

Investigate whether Coxsackievirus:

  • directly causes muscle injury;
  • mimics inflammatory myopathy;
  • triggers autoimmune muscle disease in susceptible hosts.

Do not assume universal causality.

101. RHABDOMYOLYSIS

Study:

  • severe muscle breakdown;
  • CK;
  • myoglobin;
  • acute kidney injury;
  • electrolytes;
  • viral serotype.

102. ABNORMAL MUSCLE FATIGABILITY

Use:

  • repeated contraction;
  • dynamometry;
  • EMG;
  • motor-unit analysis;
  • muscle oxygenation;
  • recovery kinetics;
  • metabolic testing;
  • 31P-MRS.

Determine whether abnormal fatigability arises from:

  • central motor pathways;
  • anterior horn;
  • peripheral motor nerve;
  • neuromuscular junction;
  • muscle;
  • mixed mechanisms.

103. PLEURODYNIA / BORNHOLM DISEASE

Investigate:

  • intercostal muscle inflammation;
  • severe chest-wall pain;
  • viral type;
  • concurrent myocarditis/pericarditis;
  • subsequent neurological disease.

104. COSTOCHONDRITIS / TIETZE-LIKE DISEASE

Prospectively investigate in laboratory-characterised EV cohorts.

Determine whether chest-wall pain reflects:

  • intercostal myositis;
  • costochondral inflammation;
  • residual inflammatory injury;
  • persistent virus;
  • unrelated musculoskeletal pathology.

PART XXV — CARDIAC DISEASE

105. MYOCARDITIS

Use:

  • ECG;
  • troponin;
  • BNP/NT-proBNP;
  • echocardiography;
  • cardiac MRI;
  • rhythm monitoring.

Determine:

  • direct viral injury;
  • viral persistence;
  • immune injury;
  • fibrosis;
  • ventricular dysfunction.

106. PERICARDITIS

Study:

  • acute pericardial inflammation;
  • recurrent disease;
  • virological evidence;
  • myocardial overlap.

107. MYOPERICARDITIS / PERIMYOCARDITIS

Define myocardial versus pericardial predominance and follow:

  • ventricular function;
  • fibrosis;
  • rhythm abnormalities.

108. PERSISTENT MYOCARDIAL ENTEROVIRUS

Where biopsy is independently clinically indicated:

  • histology;
  • PCR;
  • sequencing;
  • ISH;
  • viral protein;
  • inflammatory infiltrates;
  • fibrosis.

109. DILATED CARDIOMYOPATHY

Investigate:

ENTEROVIRUS

↓

MYOCARDITIS

↓

CLEARANCE OR PERSISTENCE

↓

CHRONIC IMMUNE INJURY

↓

FIBROSIS

↓

VENTRICULAR REMODELLING

↓

DILATED CARDIOMYOPATHY.

110. ARRHYTHMIA / CONDUCTION DISEASE

Study:

  • atrial arrhythmias;
  • ventricular arrhythmias;
  • ectopy;
  • conduction block;
  • autonomic contribution.

111. ENDOCARDITIS ASSOCIATION

Retain as carefully adjudicated exploratory/differential research.

Do not presume enterovirus is a routine cause of infective endocarditis.

PART XXVI — PANCREAS / TYPE 1 DIABETES

112. COXSACKIE B PANCREATITIS

Study:

  • acute pancreatitis;
  • recurrent pancreatitis;
  • chronic pancreatic inflammation;
  • acinar-cell injury;
  • viral persistence;
  • fibrosis;
  • repair.

113. TYPE 1 DIABETES

Test the pathway:

ENTEROVIRUS EXPOSURE

↓

PANCREATIC INFECTION

↓

INNATE IMMUNE RESPONSE

↓

BETA-CELL STRESS

↓

HLA-I / ANTIGEN-PRESENTATION CHANGES

↓

ISLET AUTOIMMUNITY

↓

BETA-CELL LOSS

↓

TYPE 1 DIABETES.

Recognise that this is an active mechanistic research area and not proof that enterovirus causes every case of T1D.

114. PANCREATITIS → LOCAL IMMUNITY → T1D

Determine whether exocrine pancreatic inflammation can promote:

  • local innate immune activation;
  • beta-cell stress;
  • neoantigen generation;
  • autoimmune islet injury.

PART XXVII — THYROID / ENDOCRINE / HOMEOSTASIS

115. PRIMARY THYROID FAILURE

Study:

  • TSH;
  • FT4;
  • FT3 where appropriate;
  • thyroid antibodies;
  • ultrasound;
  • gland volume;
  • vascularity.

116. HASHIMOTO THYROIDITIS

Investigate:

  • thyroid antibodies;
  • viral RNA/protein where tissue is clinically available;
  • receptor expression;
  • interferon response;
  • HLA-I expression;
  • lymphocytic infiltration;
  • thyroid destruction.

Do not presume enterovirus causation.

117. THYROID ATROPHY

Test longitudinally:

THYROID INFLAMMATION → IMMUNE INJURY → FOLLICULAR LOSS → REDUCED THYROID VOLUME → THYROID FAILURE.

118. SUBACUTE THYROIDITIS

Investigate Coxsackie/Echovirus links as an unresolved viral-trigger hypothesis.

119. LOW-T3 / NON-THYROIDAL ILLNESS SYNDROME

Keep this distinct from primary thyroid failure.

Differentiate:

  • primary hypothyroidism;
  • Hashimoto;
  • thyroid atrophy;
  • central hypothyroidism;
  • medication effects;
  • malnutrition;
  • severe systemic illness.

Measure:

  • TSH;
  • FT4;
  • FT3;
  • reverse T3 where scientifically justified;
  • cortisol;
  • inflammatory markers;
  • nutritional status;
  • hepatic function;
  • renal function.

Study:

  • altered T4→T3 conversion;
  • deiodinases;
  • cytokine effects;
  • reduced calorie intake;
  • systemic stress.

LOW T3 DOES NOT AUTOMATICALLY MEAN PRIMARY THYROID FAILURE.

120. CORTISOL RESPONSE TO PHYSIOLOGICAL STRESS

Study:

  • morning cortisol;
  • ACTH;
  • cortisol awakening response;
  • stimulated cortisol;
  • stress response.

Differentiate:

  • hypothalamic dysfunction;
  • pituitary dysfunction;
  • adrenal disease;
  • medication effect;
  • chronic-illness effects.

121. CIRCADIAN-RHYTHM DISRUPTION

Study:

  • cortisol rhythm;
  • melatonin rhythm;
  • core temperature;
  • sleep/wake timing;
  • BP;
  • HRV;
  • endocrine rhythmicity.

Relate abnormalities to:

  • hypothalamic injury;
  • brainstem disease;
  • autonomic dysfunction.

122. JOHN RICHARDSON BUSPIRONE / PROLACTIN STIMULATION TEST

Revisit this as a historical neuroendocrine research hypothesis.

Investigate whether buspirone-provoked prolactin responses reproducibly identify abnormalities in:

  • central serotonergic signalling;
  • hypothalamic function;
  • prolactin regulation;
  • neuroendocrine signalling.

Require:

  • standardised buspirone dosing;
  • standardised prolactin sampling;
  • medication controls;
  • healthy controls;
  • neurological disease controls;
  • endocrine controls;
  • blinded replication;
  • reproducibility.

It should not be treated as an established diagnostic test unless validated prospectively.

PART XXVIII — SEROTONIN / DOPAMINE

123. SEROTONERGIC BRAINSTEM SYSTEM

Investigate:

  • raphe nuclei;
  • serotonergic projections;
  • synthesis;
  • metabolites;
  • receptor biology;
  • transporter biology;
  • autonomic serotonin signalling;
  • GI serotonin signalling.

Do not infer central serotonin status from a nonspecific peripheral assay.

124. DOPAMINERGIC SYSTEM

Study:

  • substantia nigra;
  • basal ganglia;
  • hypothalamic dopamine;
  • motor control;
  • motivation/reward circuitry;
  • prolactin regulation;
  • autonomic interactions.

Avoid using peripheral dopamine as a direct proxy for brain dopamine.

PART XXIX — LYMPHOID / IMMUNE / HAEMATOLOGICAL DISEASE

125. RECURRENT LYMPHADENOPATHY

Investigate:

  • cervical lymph nodes;
  • mesenteric lymph nodes;
  • generalised lymphadenopathy.

Determine whether recurrent enlargement reflects:

  • persistent virus;
  • repeated infection;
  • persistent antigen;
  • immune activation;
  • autoimmune disease;
  • malignancy or another differential.

126. PROLONGED FEVER

Characterise objectively documented prolonged fever in confirmed enterovirus disease.

Track:

  • viral load;
  • inflammatory markers;
  • organ involvement;
  • other infectious differentials.

127. LEUKOPENIA

Study:

  • timing;
  • severity;
  • recovery;
  • marrow relationship;
  • viral load.

128. LYMPHOPENIA

Study:

  • total lymphocytes;
  • B cells;
  • T-cell subsets;
  • NK cells where justified;
  • disease severity;
  • persistence.

129. BONE-MARROW SUPPRESSION / FAILURE

Investigate only objectively demonstrated cases.

Use:

  • CBC;
  • reticulocytes;
  • marrow investigation where indicated;
  • viral testing;
  • immune profiling.

130. AUTOIMMUNE HAEMOLYTIC ANAEMIA

Include rare temporally associated cases, including EV-A71-associated reports, in surveillance.

Measure:

  • haemoglobin;
  • reticulocytes;
  • bilirubin;
  • LDH;
  • haptoglobin;
  • DAT;
  • blood film.

PART XXX — AUTOIMMUNE GASTRITIS / PERNICIOUS ANAEMIA / B12

131. AUTOIMMUNE GASTRITIS

Investigate:

  • gastric atrophy;
  • parietal-cell antibodies;
  • intrinsic-factor antibodies;
  • gastrin;
  • histology;
  • gastric viral material where clinically obtained.

132. PERNICIOUS ANAEMIA

Treat pernicious anaemia specifically as late-stage autoimmune gastric disease impairing intrinsic-factor-mediated B12 absorption.

Do not use the label for all B12 deficiency.

133. VITAMIN B12 DEFICIENCY

Differentiate:

  • pernicious anaemia;
  • terminal-ileal malabsorption;
  • other malabsorption;
  • poor intake;
  • severe GI dysmotility;
  • medication-related deficiency.

Measure:

  • serum B12;
  • methylmalonic acid;
  • homocysteine;
  • CBC.

PART XXXI — AUTOIMMUNITY / RHEUMATOLOGY

134. ENTEROVIRUS-TRIGGERED AUTOIMMUNITY

Investigate:

  • molecular mimicry;
  • cross-reactive antibodies;
  • cross-reactive T cells;
  • epitope spreading;
  • bystander activation;
  • persistent antigen;
  • HLA susceptibility;
  • loss of immune tolerance.

135. ARTHRALGIA

Characterise:

  • joint distribution;
  • inflammatory features;
  • temporal relationship to infection;
  • persistence.

136. ARTHRITIS

Differentiate:

  • direct viral arthritis;
  • transient post-infectious arthritis;
  • reactive arthritis;
  • evolving autoimmune inflammatory arthritis.

137. SERONEGATIVE POLYARTHRITIS

Prospectively measure:

  • RF;
  • anti-CCP;
  • ANA;
  • ENA;
  • complement;
  • CRP/ESR;
  • HLA;
  • ultrasound/MRI;
  • synovial fluid where appropriate.

Determine whether cases represent:

  • transient infection-associated arthritis;
  • post-infectious immune arthritis;
  • evolving chronic inflammatory disease.

138. PALINDROMIC RHEUMATISM

Investigate episodic inflammatory joint attacks following defined enterovirus infection.

Track:

  • recurrence;
  • attack duration;
  • remission;
  • anti-CCP/RF status;
  • progression to rheumatoid arthritis;
  • other autoimmune disease.

Do not presume enterovirus causality.

139. MIXED CONNECTIVE-TISSUE DISEASE

Investigate as a post-infectious/immune association in susceptible individuals.

Measure:

  • ANA;
  • anti-U1-RNP;
  • ENA;
  • complement;
  • inflammatory markers;
  • longitudinal virology.

140. LUPUS / SYSTEMIC-SCLEROSIS / OTHER CONNECTIVE-TISSUE DISEASE

Retain exploratory workstreams into whether infection:

  • triggers;
  • modifies;
  • exacerbates

autoimmune connective-tissue disease.

141. MYASTHENIA GRAVIS

Investigate:

  • AChR antibodies;
  • MuSK;
  • LRP4 where appropriate;
  • repetitive nerve stimulation;
  • single-fibre EMG.

Differentiate MG from:

  • brainstem encephalitis;
  • anterior-horn disease;
  • cranial neuropathy;
  • myositis.

142. FIBROMYALGIA

Use primarily as:

  • comparator cohort;
  • chronic pain phenotype;
  • central-sensitisation comparator.

If a biologically distinct enterovirus-associated subgroup exists, demonstrate it with objective virological evidence rather than symptom overlap.

PART XXXII — MAST-CELL ACTIVATION / INTOLERANCES

143. OBJECTIVELY CONFIRMED MAST-CELL ACTIVATION

Determine whether abnormal mast-cell activation occurs in a defined subset after enteroviral neurological disease.

Investigate:

  • tryptase;
  • histamine pathways;
  • prostaglandin metabolites;
  • leukotriene metabolites;
  • cytokine signalling;
  • mast-cell/endothelial interactions;
  • mast-cell/nerve interactions;
  • mast-cell/GI interactions.

Do not diagnose MCAS from nonspecific symptoms alone.

144. FOOD INTOLERANCE

Differentiate:

  • IgE-mediated food allergy;
  • mast-cell-mediated reaction;
  • histamine-related hypotheses;
  • enzyme deficiency;
  • GI dysmotility;
  • autonomic GI dysfunction;
  • malabsorption;
  • inflammatory bowel disease;
  • poor gastric emptying.

145. DRUG INTOLERANCE

Investigate:

  • true allergy;
  • mast-cell pathways;
  • pharmacokinetics;
  • altered autonomic haemodynamics;
  • liver metabolism;
  • renal clearance;
  • drug interactions;
  • CNS sensitivity.

146. ALCOHOL INTOLERANCE

Study:

  • vasodilation;
  • orthostatic effects;
  • objectively measured blood volume;
  • cerebral perfusion;
  • acetaldehyde metabolism;
  • mast-cell/histamine pathways;
  • medication interactions.

PART XXXIII — GENITOURINARY / REPRODUCTIVE

147. EPIDIDYMITIS

Investigate acute inflammatory disease where enterovirus is virologically supported.

148. ORCHITIS

Study:

  • acute inflammation;
  • tissue injury;
  • testicular function;
  • fertility consequences;
  • persistent viral material where clinically obtainable.

149. PROSTATITIS

Retain as exploratory unless supported by direct virological evidence.

150. SALPINGITIS

Investigate possible infection-associated reproductive inflammatory disease without assuming causation.

151. ENDOMETRIOSIS

Maintain as an explicitly exploratory infection/immunity/inflammation association.

Study:

  • pelvic immune activation;
  • angiogenesis;
  • endothelial signalling;
  • fibroblast activation;
  • fibrosis;
  • neuroimmune pain.

Do not present enterovirus as an established cause of endometriosis.

PART XXXIV — CROHN’S / IBD

152. CROHN’S DISEASE

Investigate:

  • EV RNA/protein;
  • intestinal epithelial infection;
  • terminal ileum;
  • Peyer’s patches;
  • mucosal immunity;
  • Paneth-cell biology;
  • autophagy;
  • intestinal permeability;
  • microbiome;
  • virome;
  • disease flares.

Distinguish:

  • incidental viral detection;
  • disease modification;
  • true causal mechanism.

PART XXXV — ADULT / NEONATAL SEPSIS AND SYSTEMIC DISEASE

153. ADULT ENTEROVIRUS SEPSIS / SEPSIS-LIKE DISEASE

Investigate severe adult systemic EV infection involving:

  • shock;
  • hypotension;
  • myocarditis;
  • hepatitis;
  • pneumonia;
  • encephalitis;
  • renal dysfunction;
  • coagulopathy;
  • multi-organ failure.

Collect:

  • blood EV testing;
  • respiratory/stool/CSF specimens where indicated;
  • whole-genome sequencing;
  • inflammatory markers;
  • organ-specific biomarkers.

154. NEONATAL ENTEROVIRUS SEPSIS

Create permanent surveillance for:

  • sepsis-like illness;
  • myocarditis;
  • hepatitis;
  • coagulopathy;
  • meningoencephalitis;
  • pneumonia;
  • respiratory failure;
  • shock;
  • multi-organ failure;
  • death.

Develop:

  • rapid neonatal pan-EV PCR;
  • urgent serotyping;
  • rapid sequence analysis;
  • investigational antiviral pathways;
  • antibody/IVIG research.

PART XXXVI — ACUTE NEUROINFLAMMATION

155. DEFINE WHAT IS CAUSING ACUTE TISSUE INJURY

Distinguish:

  • direct viral replication;
  • virus-driven innate immune inflammation;
  • secondary immune-mediated injury;
  • complement activation;
  • endothelial inflammation;
  • BBB/BSCB disruption;
  • mixed viral and immune pathology.

156. ACUTE ANTI-INFLAMMATORY DRUG DEVELOPMENT

Create a dedicated medicinal and translational pharmacology programme rather than depending only on broad nonspecific immunosuppression.

Potential targets:

  • inflammasomes;
  • microglial activation;
  • astrocyte activation;
  • defined cytokines;
  • chemokines;
  • complement;
  • leukocyte trafficking;
  • endothelial activation;
  • oxidative injury;
  • excitotoxicity;
  • BBB/BSCB permeability.

Central principle:

SUPPRESS DAMAGING INFLAMMATION WITHOUT LOSING CONTROL OF THE VIRUS.

157. ANTIVIRAL + ANTI-INFLAMMATORY COMBINATION TRIALS

Compare:

  • antiviral alone;
  • targeted anti-inflammatory alone;
  • antiviral + targeted anti-inflammatory;
  • antiviral + neuroprotection;
  • antiviral + immune treatment.

Use objective endpoints:

  • viral burden;
  • inflammatory biomarkers;
  • MRI;
  • neurophysiology;
  • neurological outcome;
  • autonomic outcome;
  • organ outcomes.

PART XXXVII — CHRONIC / ONGOING NEUROINFLAMMATION

158. DEFINE THE DRIVER

Distinguish:

  • persistent EV;
  • persistent viral antigen;
  • microglial activation;
  • astrocyte activation;
  • post-infectious autoimmunity;
  • BBB/endothelial inflammation;
  • peripheral-nerve immune injury;
  • residual structural damage;
  • mixed pathology.

159. CHRONIC NEUROINFLAMMATION TREATMENT

Develop mechanism-specific approaches against:

  • microglia;
  • astrocytes;
  • cytokines;
  • chemokines;
  • complement;
  • endothelial inflammation;
  • leukocyte trafficking;
  • BBB dysfunction;
  • B-cell/plasma-cell pathology;
  • pathogenic autoantibodies.

Avoid indiscriminate long-term immunosuppression where persistent infection has not been excluded.

PART XXXVIII — HIV/HCV-STYLE ENTEROVIRUS ANTIVIRAL DEVELOPMENT

160. BUILD A COMPLETE ANTIVIRAL DRUG-DEVELOPMENT ECOSYSTEM

The roadmap should learn structurally from what transformed HIV and hepatitis C treatment.

The aim should not be:

FIND ONE DRUG.

The aim should be:

CREATE MULTIPLE INDEPENDENT ANTIVIRAL CLASSES

USE COMBINATION THERAPY

QUANTIFY VIRAL BURDEN

TEST RESISTANCE

MEASURE TISSUE PENETRATION

DEVELOP SECOND-LINE / SALVAGE REGIMENS

TREAT TO VIROLOGICAL ENDPOINTS WHERE POSSIBLE.

161. ATTACHMENT / RECEPTOR BLOCKERS

Develop therapies targeting:

  • receptor binding;
  • viral attachment;
  • cellular entry;
  • receptor-dependent tropism.

Study receptor biology across:

  • neural tissue;
  • muscle;
  • myocardium;
  • pancreatic tissue;
  • gut;
  • respiratory epithelium.

162. CAPSID INHIBITORS

Develop next-generation capsid inhibitors with improved:

  • potency;
  • breadth;
  • pharmacokinetics;
  • safety;
  • CNS penetration;
  • resistance barrier.

Study:

  • attachment interference;
  • capsid stabilisation;
  • prevention of uncoating.

163. UNCOATING INHIBITORS

Target the process by which EV releases genomic RNA into the host cell.

Combine with other antiviral classes to reduce resistance.

164. 2A PROTEASE INHIBITORS

Develop specific enterovirus 2A inhibitors.

Assess:

  • antiviral potency;
  • serotype breadth;
  • host-protein effects;
  • CNS penetration;
  • GI penetration;
  • cardiac penetration;
  • resistance.

165. 2C INHIBITORS

Target 2C functions involved in:

  • viral replication;
  • membrane-associated replication;
  • other essential lifecycle processes.

Pursue broad-spectrum compounds where possible.

166. 3C PROTEASE INHIBITORS

Create a major 3C medicinal-chemistry platform.

Optimise:

  • potency;
  • selectivity;
  • oral bioavailability;
  • CNS penetration;
  • tissue distribution;
  • resistance barrier.

167. 3D POLYMERASE INHIBITORS

Develop:

  • nucleoside analogues;
  • non-nucleoside inhibitors;
  • chain-termination approaches;
  • high-resistance-barrier compounds.

168. HOST-FACTOR ANTIVIRALS

Identify host factors essential to:

  • viral translation;
  • replication;
  • membrane remodelling;
  • assembly;
  • release.

Do not pursue host targets with unacceptable human toxicity.

169. BROAD-SPECTRUM ENTEROVIRUS ANTIVIRALS

Develop agents covering multiple:

  • Coxsackie A viruses;
  • Coxsackie B viruses;
  • Echoviruses;
  • EV-A71;
  • EV-D68;
  • emerging neurotropic types.

170. COMBINATION ANTIVIRAL THERAPY

Test:

  • dual therapy;
  • triple therapy;
  • induction regimens;
  • consolidation regimens;
  • sequential treatment.

Example mechanistic combinations:

ENTRY/CAPSID INHIBITOR

PROTEASE INHIBITOR

POLYMERASE INHIBITOR.

Determine whether combination therapy:

  • suppresses replication faster;
  • reduces resistance;
  • clears persistent compartments;
  • reduces relapse;
  • prevents neurological progression.

171. ANTIVIRAL RESISTANCE NETWORK

Sequence virus:

  • before treatment;
  • during treatment;
  • at virological breakthrough;
  • after relapse.

Develop:

  • resistance-associated mutation databases;
  • phenotypic susceptibility testing;
  • cross-resistance maps;
  • treatment-history registries.

172. SALVAGE THERAPY

Develop second-line and third-line combinations for:

  • resistant infection;
  • treatment failure;
  • relapsing persistent infection.

173. VIRAL-LOAD-GUIDED TREATMENT

Create validated quantitative endpoints:

  • baseline viral burden;
  • rate of decline;
  • suppression;
  • tissue clearance;
  • rebound;
  • treatment failure.

174. TISSUE-PENETRATION PHARMACOLOGY

A useful antiviral must reach the reservoir.

Measure drug exposure in or model penetration into:

  • CSF;
  • CNS;
  • spinal cord;
  • DRG;
  • autonomic ganglia;
  • skeletal muscle;
  • myocardium;
  • GI tissue;
  • pancreatic tissue;
  • peripheral nerves.

175. ACUTE VS PERSISTENT / NON-CYTOLYTIC ENTEROVIRUS PHARMACOLOGY

Do not assume drugs effective in acute lytic infection will work against persistent viral states.

Develop models of:

  • low-level replication;
  • non-cytolytic infection;
  • defective genomes;
  • altered viral RNA;
  • intracellular persistence.

176. TREATMENT-DURATION RESEARCH

Determine whether different diseases require:

  • short acute therapy;
  • several weeks;
  • prolonged therapy;
  • induction + consolidation;
  • combination treatment until objective virological suppression/clearance.

PART XXXIX — RNA / GENE / BIOLOGIC ANTIVIRALS

177. ANTISENSE / siRNA / RNA-INTERFERENCE THERAPEUTICS

Target conserved enterovirus RNA sequences.

Research:

  • tissue delivery;
  • resistance;
  • off-target toxicity;
  • CNS delivery;
  • persistence models.

178. CRISPR-BASED ANTIVIRAL RESEARCH

Explore RNA-targeting CRISPR or related technologies where scientifically and clinically feasible.

This is long-horizon experimental research rather than an established treatment.

179. NEUTRALISING MONOCLONAL ANTIBODIES

Identify:

  • type-specific neutralising antibodies;
  • broadly neutralising antibodies.

Potential use:

  • neonatal prophylaxis;
  • outbreak prophylaxis;
  • immunocompromised patients;
  • early severe neurological infection;
  • adjunct to antiviral therapy.

PART XL — IMMUNOGLOBULIN

180. IVIG AT ACUTE NEUROLOGICAL ONSET

Conduct controlled trials in biologically characterised severe enterovirus neurological disease.

Study:

  • timing;
  • dose;
  • neutralising-antibody content;
  • viral load;
  • inflammatory biomarkers;
  • neurological outcome;
  • adverse effects.

Do not presume benefit from uncontrolled experience.

181. IVIG / SCIG AS ANTIVIRAL ANTIBODY REPLACEMENT

Study especially in:

  • hypogammaglobulinaemia;
  • B-cell depletion;
  • impaired humoral immunity;
  • recurrent/persistent EV disease;
  • inadequate neutralising antibody.

Measure:

  • serum IgG;
  • subclasses;
  • EV-neutralising titres;
  • viral load;
  • CSF virology where appropriate;
  • clinical clearance.

182. IVIG AS IMMUNOMODULATION

Keep separate from passive antiviral antibody replacement.

Study in appropriately defined:

  • GBS;
  • MFS;
  • immune neuropathy;
  • autonomic autoimmunity;
  • inflammatory myopathy;
  • autoimmune haemolytic anaemia;
  • other antibody/complement-mediated disease.

PART XLI — PRECISION IMMUNOMODULATION

183. MOVE BEYOND NONSPECIFIC IMMUNOSUPPRESSION

Develop targeted therapies according to demonstrated biology.

Potential targets:

  • cytokines;
  • chemokines;
  • complement;
  • Fc receptors;
  • B cells;
  • plasma cells;
  • autoreactive T cells;
  • microglia;
  • astrocytes;
  • endothelial inflammation.

184. B-CELL THERAPIES

Potential pathways:

  • CD20;
  • CD19;
  • BAFF;
  • APRIL.

But monitor:

  • IgG;
  • EV-neutralising antibody;
  • persistent-virus risk;
  • viral reactivation.

Persistent enterovirus must be carefully considered before suppressing humoral immunity.

185. PLASMA-CELL THERAPIES

For genuinely demonstrated pathogenic autoantibody disease, investigate plasma-cell-targeting approaches.

Balance against the need to preserve antiviral antibody immunity.

186. T-CELL-DIRECTED THERAPIES

Develop only where autoreactive/pathogenic T-cell responses are objectively demonstrated.

187. COMPLEMENT INHIBITION

Study in biologically demonstrated complement-mediated:

  • neurological disease;
  • vascular disease;
  • autoimmune disease.

188. ANTIGEN-SPECIFIC IMMUNE TOLERANCE

Long-term goal:

CONTROL PATHOGENIC AUTOIMMUNITY WITHOUT DISABLING NORMAL ANTIVIRAL IMMUNITY.

Research:

  • tolerogenic peptides;
  • tolerogenic dendritic cells;
  • regulatory T cells;
  • antigen-specific immune retraining.

PART XLII — AUTOANTIBODY DISCOVERY

189. SYSTEMATIC AUTOANTIBODY DISCOVERY PLATFORM

Search for autoantibodies directed against:

  • neuronal proteins;
  • gangliosides;
  • autonomic receptors;
  • nodal/paranodal proteins;
  • ion channels;
  • muscle targets;
  • cardiac targets;
  • endothelial targets;
  • other biologically relevant proteins.

Use:

  • antigen/protein arrays;
  • phage-display technologies;
  • immunoprecipitation;
  • mass spectrometry;
  • cell-based assays;
  • CSF autoantibody analysis.

190. FUNCTIONAL VALIDATION OF AUTOANTIBODIES

Detection alone is not enough.

Demonstrate:

  • receptor activation;
  • receptor blockade;
  • ion-channel dysfunction;
  • neuronal effects;
  • autonomic effects;
  • endothelial effects;
  • passive-transfer effects where scientifically appropriate.

PART XLIII — PLASMAPHERESIS / IMMUNOADSORPTION

191. MODERN THERAPEUTIC PLASMA EXCHANGE

Develop disease-specific PLEX protocols for confirmed antibody-mediated disease.

Study:

  • exchange volume;
  • number of exchanges;
  • interval;
  • response kinetics;
  • rebound;
  • infection risk;
  • coagulation effects;
  • line complications.

192. IMMUNOADSORPTION

Develop more selective antibody-removal technologies.

Research:

  • IgG adsorption;
  • IgM adsorption;
  • broad immunoglobulin adsorption;
  • pathogen-specific or autoantibody-specific approaches.

Determine whether immunoadsorption can preserve more normal plasma components than conventional plasma exchange.

193. ANTIGEN-SPECIFIC IMMUNOADSORPTION

Long-term goal:

REMOVE THE PATHOGENIC AUTOANTIBODY WHILE LEAVING THE REST OF HUMORAL IMMUNITY AS INTACT AS POSSIBLE.

Develop antigen-specific columns where the relevant pathogenic antibody has been validated.

194. AUTOANTIBODY-REBOUND PREVENTION

Because PLEX or adsorption removes antibodies without necessarily stopping their production:

RAPID AUTOANTIBODY REMOVAL

↓

CONTROL PATHOGENIC B-CELL / PLASMA-CELL PRODUCTION

↓

RESTORE IMMUNE TOLERANCE

↓

LONGITUDINAL AUTOANTIBODY MONITORING.

PART XLIV — RINTATOLIMOD / AMPLIGEN

195. RINTATOLIMOD ENTEROVIRUS-SPECIFIC RESEARCH

Do not simply extrapolate from broad CFS/ME cohorts.

Create biologically defined trials:

TRIAL A — ACUTE / RECENT ENTEROVIRUS

TRIAL B — LAB-CONFIRMED PERSISTENT ENTEROVIRUS

TRIAL C — PERSISTENT EV + ABNORMAL INTERFERON/TLR3 BIOLOGY

TRIAL D — POST-CLEARANCE IMMUNE DYSREGULATION.

Measure:

  • EV RNA;
  • viral protein;
  • viral load;
  • tissue persistence;
  • TLR3 signalling;
  • interferon pathways;
  • inflammatory markers;
  • neurological outcome;
  • autonomic outcome;
  • muscle outcome.

PART XLV — HUMAN CELL / ORGANOID MODELS

196. HUMAN CELL MODELS

Develop:

  • cortical neurons;
  • motor neurons;
  • brainstem neurons;
  • sensory neurons;
  • autonomic neurons;
  • DRG neurons;
  • Schwann cells;
  • oligodendrocytes;
  • astrocytes;
  • microglia;
  • skeletal muscle;
  • cardiomyocytes;
  • endothelial cells;
  • intestinal epithelial cells;
  • enteric neurons;
  • pancreatic cells;
  • thyroid cells.

197. ORGANOID PLATFORM

Develop:

  • brain organoids;
  • brainstem organoids;
  • spinal-cord organoids;
  • motor-neuron organoids;
  • DRG/sensory models;
  • peripheral-nerve models;
  • skeletal-muscle organoids;
  • cardiac organoids;
  • intestinal organoids;
  • pancreatic organoids;
  • thyroid organoids.

Use them to model:

ACUTE INFECTION

↓

PERSISTENCE

↓

INFLAMMATION

↓

AUTOIMMUNITY

↓

TISSUE DAMAGE

↓

ANTIVIRAL TREATMENT

↓

IMMUNOMODULATION

↓

REGENERATION.

PART XLVI — TISSUE BANK

198. BRAIN / SPINAL-CORD / MULTI-ORGAN TISSUE BANK

Collect ethically and clinically appropriate:

  • brain;
  • brainstem;
  • spinal cord;
  • DRG;
  • peripheral nerve;
  • skeletal muscle;
  • heart;
  • stomach;
  • small intestine;
  • terminal ileum;
  • lymphoid tissue;
  • pancreas;
  • thyroid;
  • vascular tissue.

Use:

  • histology;
  • IHC;
  • ISH;
  • PCR;
  • WGS;
  • spatial transcriptomics;
  • single-cell sequencing;
  • proteomics;
  • immune profiling;
  • electron microscopy.

PART XLVII — STEM CELLS / REGENERATIVE MEDICINE

199. STEM-CELL RESEARCH PROGRAMME

Create a dedicated regenerative-medicine arm.

Use stem-cell technologies for:

  • disease modelling;
  • antiviral screening;
  • drug-toxicity screening;
  • tissue repair research;
  • neuronal regeneration;
  • cardiac repair;
  • vascular repair.

Do not present unproven commercial stem-cell treatment as established therapy.

200. iPSC DISEASE MODELS

Generate patient-derived and control:

  • motor neurons;
  • sensory neurons;
  • autonomic neurons;
  • Schwann cells;
  • oligodendrocytes;
  • cardiomyocytes;
  • endothelial cells;
  • intestinal neurons.

Study:

  • viral susceptibility;
  • persistence;
  • host genetics;
  • treatment response.

201. NEURAL STEM / PROGENITOR CELLS

Investigate whether cell-based strategies can support recovery after:

  • spinal-cord injury;
  • anterior-horn injury;
  • brainstem injury;
  • severe peripheral-nerve injury.

Measure:

  • neuronal survival;
  • axonal growth;
  • synaptic integration;
  • reinnervation;
  • functional recovery.

202. MOTOR-NEURON REPLACEMENT / SUPPORT

Long-term research into:

  • stem-cell-derived motor neurons;
  • supportive glia;
  • neurotrophic support;
  • replacement/support of severely damaged anterior-horn circuitry.

203. SCHWANN-CELL / PERIPHERAL-NERVE REGENERATION

Combine:

  • Schwann-cell biology;
  • progenitor cells;
  • nerve conduits;
  • nerve grafts;
  • neurotrophic factors;
  • electrical stimulation;
  • rehabilitation.

204. OLIGODENDROCYTE / REMYELINATION PROGRAMME

Develop:

  • oligodendrocyte-progenitor approaches;
  • pharmacological remyelination;
  • nodal/paranodal repair.

205. AUTONOMIC-NEURON REGENERATION

Study regeneration of:

  • sympathetic;
  • parasympathetic;
  • sudomotor;
  • vasomotor;
  • enteric;
  • cardiac autonomic pathways.

206. CARDIAC REGENERATIVE MEDICINE

Study:

  • cardiomyocyte repair;
  • myocardial regeneration;
  • fibrosis reversal;
  • stem/progenitor strategies;
  • vascular support

following enteroviral myocarditis/DCM.

207. ENDOTHELIAL / PERICYTE REGENERATION

Develop strategies to restore:

  • BBB integrity;
  • microvascular function;
  • cerebral perfusion;
  • vasa nervorum;
  • myocardial microcirculation.

PART XLVIII — CNS / MOTOR / PERIPHERAL NERVE REPAIR

208. CNS REPAIR

Research:

  • neuroprotection;
  • axonal sprouting;
  • synaptic recovery;
  • remyelination;
  • neurotrophic support;
  • neuroplastic rehabilitation.

209. MOTOR-NEURON / ANTERIOR-HORN REPAIR

Study:

  • motor-neuron preservation;
  • collateral reinnervation;
  • motor-unit enlargement;
  • muscle reinnervation;
  • prevention of secondary muscle atrophy;
  • respiratory-motor recovery.

210. SMALL-FIBRE REGENERATION

Develop:

  • neurotrophic approaches;
  • axonal growth;
  • Schwann support;
  • microvascular repair;
  • removal of persistent infectious or immune injury.

211. LARGE-FIBRE AXONAL REPAIR

Study:

  • axonal regeneration;
  • remyelination;
  • nodal/paranodal repair;
  • Schwann-cell biology;
  • rehabilitation.

212. BRACHIAL-PLEXUS / UPPER-LIMB REINNERVATION

Investigate:

  • nerve transfers;
  • collateral reinnervation;
  • muscle reinnervation;
  • functional electrical stimulation;
  • targeted rehabilitation.

PART XLIX — EXPLORATORY TUMOUR BIOLOGY

213. GENERAL TUMOUR-RESEARCH RULE

ENTEROVIRUSES ARE NOT ESTABLISHED HUMAN ONCOVIRUSES.

Any tumour association therefore requires much stronger evidence than incidental PCR positivity.

214. THYROID CANCER

Investigate:

  • viral RNA;
  • viral protein;
  • sequence;
  • tumour localisation;
  • adjacent tissue;
  • thyroiditis history.

215. BREAST CANCER

Maintain exploratory tissue surveillance with localisation rather than bulk-PCR inference.

216. ASTROCYTOMA / GLIOMA

Study:

  • viral RNA;
  • viral protein;
  • viral sequence;
  • astrocyte/tumour-cell localisation;
  • inflammatory microenvironment;
  • endothelial/stromal involvement.

217. RETROPERITONEAL TUMOURS

Retain rare exploratory surveillance within the longitudinal registry.

218. TUMOUR MICROENVIRONMENT

Where viral material is detected, determine whether it is actually located in:

  • tumour cells;
  • epithelial cells;
  • endothelial cells;
  • fibroblasts;
  • infiltrating leukocytes.

Use:

  • ISH;
  • spatial transcriptomics;
  • single-cell analysis;
  • viral capture sequencing.

PART L — SPECIALIST SERVICES

219. SPECIALIST ENTEROVIRAL DISEASE CENTRES

Integrate:

  • Neurology;
  • Infectious Diseases;
  • Virology;
  • Neuropathology;
  • Neuroradiology;
  • Neuromuscular Medicine;
  • Peripheral-Nerve Medicine;
  • Autonomic Medicine;
  • Cardiology;
  • Vascular Medicine;
  • Gastroenterology;
  • Intestinal Failure;
  • Nutrition;
  • Endocrinology;
  • Rheumatology;
  • Immunology;
  • Haematology;
  • Pain Medicine;
  • Audiovestibular Medicine;
  • Rehabilitation.

220. RAPID ENTEROVIRUS CLINICS

Provide:

  • urgent same-day sampling;
  • rapid pan-EV testing;
  • rapid species determination;
  • rapid serotyping;
  • sequencing pathway;
  • neurological examination;
  • respiratory assessment;
  • cardiac assessment;
  • early imaging;
  • follow-up;
  • persistent-infection testing if acute testing later becomes negative.

DO NOT WAIT UNTIL THE INFECTION HAS BECOME DIFFICULT TO DETECT.

221. PAEDIATRIC NEUROENTEROVIRUS CENTRES

Priority:

  • HFMD;
  • EV-A71;
  • EV-D68;
  • meningitis;
  • encephalitis;
  • brainstem disease;
  • rhombencephalitis;
  • AFM;
  • paralysis;
  • neonatal disease;
  • long-term motor disability.

PART LI — EDUCATION

222. RAMSAY M.E. MEDICAL EDUCATION

Teach:

  • historical outbreaks;
  • Royal Free;
  • Ramsay;
  • Dowsett;
  • sudden infectious onset;
  • CNS disease;
  • brainstem disease;
  • spinal disease;
  • motor abnormalities;
  • cranial neuropathies;
  • autonomic disease;
  • abnormal muscle fatigability;
  • enterovirus research;
  • viral persistence hypotheses;
  • importance of acute virology.

223. ENTEROVIRUS CLINICAL-SPECTRUM EDUCATION

RESPIRATORY

  • rhinosinusitis;
  • pharyngitis;
  • bronchitis;
  • bronchiolitis;
  • pleurisy;
  • pneumonia.

GASTROINTESTINAL

  • vomiting;
  • diarrhoea;
  • gastritis;
  • terminal ileitis;
  • colitis;
  • mesenteric adenitis;
  • hepatitis;
  • pancreatitis;
  • GERD;
  • functional dyspepsia;
  • gastroparesis;
  • paralytic ileus;
  • chronic intestinal pseudo-obstruction.

CNS / PNS

  • meningitis;
  • encephalitis;
  • brainstem encephalitis;
  • rhombencephalitis;
  • myelitis;
  • encephalomyelitis;
  • AFM;
  • poliomyelitis-like paralysis;
  • radiculitis;
  • brachial-plexus disease;
  • GBS;
  • Miller Fisher syndrome;
  • peripheral neuropathy.

SENSORY

  • photophobia;
  • hyperacusis;
  • tinnitus;
  • vertigo;
  • hearing loss;
  • migraine research.

MOTOR / MUSCLE

  • paresis;
  • fasciculations;
  • spasms;
  • myoclonus;
  • muscle wasting;
  • myositis;
  • rhabdomyolysis;
  • pleurodynia;
  • abnormal muscle fatigability.

CARDIAC

  • myocarditis;
  • pericarditis;
  • myopericarditis;
  • arrhythmia;
  • dilated cardiomyopathy.

RHEUMATOLOGICAL

  • arthralgia;
  • arthritis;
  • seronegative polyarthritis;
  • palindromic rheumatism;
  • connective-tissue autoimmunity.

IMMUNE / HAEMATOLOGICAL

  • prolonged fever;
  • leukopenia;
  • lymphopenia;
  • recurrent lymphadenopathy;
  • marrow suppression;
  • autoimmune haemolytic anaemia.

GENITOURINARY

  • epididymitis;
  • orchitis;
  • prostatitis;
  • salpingitis research.

SKIN / ORAL / EYE

  • HFMD;
  • herpangina;
  • enanthem;
  • mouth/tongue ulcers;
  • vesicles;
  • maculopapular rash;
  • petechiae;
  • urticaria;
  • haemorrhagic conjunctivitis.

SYSTEMIC / NEONATAL

  • sepsis-like illness;
  • myocarditis;
  • hepatitis;
  • coagulopathy;
  • meningoencephalitis;
  • pneumonia;
  • shock;
  • multi-organ failure.

224. EMERGENCY-DEPARTMENT EDUCATION

Teach emergency clinicians to recognise:

  • acute flaccid weakness;
  • severe asymmetric weakness;
  • brainstem signs;
  • bulbar dysfunction;
  • ophthalmoplegia;
  • autonomic instability;
  • myocarditis;
  • severe HFMD;
  • neonatal EV sepsis;
  • paralytic ileus;
  • severe dysphagia.

Ensure acute specimen collection before the diagnostic window closes.

225. TUBE-FEEDING / PARENTERAL-NUTRITION EDUCATION

Teach:

ORAL

↓

NG

↓

NJ

↓

PEG / RIG

↓

GJ / PEG-J

↓

DIRECT JEJUNOSTOMY

↓

PARENTERAL NUTRITION / TPN

according to clinical physiology.

226. BLOOD-VOLUME / CEREBRAL-PERFUSION EDUCATION

Teach the distinction:

BLOOD-VOLUME TESTING

directly measures circulating volume.

SEGAMI OASIS / NEUROGAM SPECT

quantitatively analyses regional cerebral perfusion.

AUTONOMIC TESTING

measures haemodynamic regulation.

These should be correlated, not conflated.

227. MAST-CELL / INTOLERANCE EDUCATION

Teach clinicians to distinguish:

  • mast-cell activation;
  • IgE allergy;
  • autonomic haemodynamic intolerance;
  • GI dysmotility;
  • medication intolerance;
  • metabolic effects.

PART LII — PATIENT GOVERNANCE

228. UK ENTEROVIRUS FOUNDATION

Create an independent organisation focused on:

  • enterovirus diagnostics;
  • rapid testing;
  • virology;
  • antivirals;
  • vaccines;
  • neurological disease;
  • cardiac disease;
  • muscle disease;
  • persistent infection;
  • neuropathy;
  • dysautonomia;
  • education;
  • patient support.

People directly injured by enterovirus disease should hold meaningful governance and voting positions.

229. MYALGIC ENCEPHALOMYELITIS ASSOCIATION ADVOCACY PROPOSAL

Restore a dedicated Historical/Ramsay M.E. remit with substantial Ramsay-M.E. patient influence over:

  • research priorities;
  • policy;
  • advocacy;
  • education;
  • scientific advisers;
  • funding;
  • strategy.

230. SEPARATE CFS / ME/CFS / SEID REPRESENTATION

Advocacy proposal:

SEPARATE ORGANISATIONS.

SEPARATE GOVERNANCE.

SEPARATE RESEARCH COHORTS.

SEPARATE FUNDING STREAMS.

TRANSPARENT DISEASE DEFINITIONS.

PART LIII — INTERNATIONAL REGISTRY / BIOBANK

231. INTERNATIONAL ENTEROVIRUS REGISTRY

Record:

  • onset;
  • infectious prodrome;
  • specimen timing;
  • acute PCR;
  • persistent blood tests;
  • serotype;
  • genome;
  • viral load;
  • CNS phenotype;
  • brainstem disease;
  • spinal disease;
  • anterior-horn disease;
  • AFM;
  • paresis;
  • radiculitis;
  • brachial-plexus phenotype;
  • GBS;
  • MFS;
  • peripheral neuropathy;
  • autonomic dysfunction;
  • blood-volume measurement;
  • cerebral-perfusion SPECT;
  • ASL-MRI;
  • GI paresis;
  • paralytic ileus;
  • muscle disease;
  • cardiac disease;
  • pancreas/T1D;
  • thyroid/endocrine abnormalities;
  • rheumatological disease;
  • autoimmune disease;
  • haematological disease;
  • mast-cell/intolerance phenotype;
  • viral persistence;
  • antivirals;
  • resistance;
  • immunoglobulin;
  • PLEX/immunoadsorption;
  • nutrition;
  • recovery;
  • relapse;
  • disability;
  • mortality.

232. REAL-TIME GENOMIC SURVEILLANCE

CLUSTER

↓

RAPID SAMPLE

↓

RAPID PAN-EV PCR

↓

VP1

↓

WHOLE-GENOME SEQUENCE

↓

PHENOTYPE

↓

SEVERITY

↓

DRUG-RESISTANCE / SUSCEPTIBILITY DATA

↓

VACCINE RELEVANCE.

233. GLOBAL OUTBREAK ALERT SYSTEM

Rapidly identify:

  • meningitis clusters;
  • encephalitis clusters;
  • brainstem disease clusters;
  • AFM clusters;
  • paralytic disease;
  • HFMD neurological outbreaks;
  • neonatal sepsis outbreaks;
  • myocarditis clusters;
  • newly emerging EV types.

PART LIV — VACCINES

234. SAFE MULTIVALENT ENTEROVIRUS VACCINES

Priority targets:

  • Coxsackie B;
  • important Echoviruses;
  • EV-A71;
  • EV-D68;
  • emerging paralytic/non-polio neurotropic EVs.

Develop:

  • multivalent vaccines;
  • conserved-antigen vaccines;
  • broad-neutralising approaches;
  • durable immunity;
  • paediatric safety;
  • adult safety;
  • neurological safety;
  • cardiac safety;
  • manufacturing scale-up.

COMPLETE RAPID DIAGNOSTIC PIPELINE

SUDDEN-ONSET INFECTIOUS ILLNESS

↓

SAMPLE IMMEDIATELY

CSF + STOOL + THROAT / RESPIRATORY + BLOOD

↓

RAPID PAN-EV RT-PCR

↓

SPECIES

A / B / C / D

↓

RAPID SEROTYPE

A7 / OTHER A / CV-B / ECHOVIRUS / A71 / D68 / D70 / OTHER

↓

QUANTITATIVE VIRAL LOAD WHERE VALIDATED

↓

WHOLE-GENOME SEQUENCE

↓

DEFINE ANATOMICAL DISEASE

MENINGITIS

ENCEPHALITIS

BRAINSTEM ENCEPHALITIS

RHOMBENCEPHALITIS

ENCEPHALOMYELITIS

MYELITIS

ANTERIOR-HORN / POLIO-LIKE DISEASE

AFM

RADICULITIS

BRACHIAL-PLEXUS DISEASE

PERIPHERAL NEUROPATHY

GBS / MFS

MYOSITIS

CARDIAC DISEASE

GI / MULTISYSTEM DISEASE

↓

BIOLOGY-MATCHED ACUTE TREATMENT

ANTIVIRAL

NEUROLOGICAL SUPPORT

RESPIRATORY SUPPORT

CARDIAC SUPPORT

TARGETED ANTI-INFLAMMATORY TREATMENT

APPROPRIATELY STUDIED IMMUNOGLOBULIN

↓

FOLLOW LONGITUDINALLY.

If virus is apparently cleared:

investigate residual:

  • CNS injury;
  • anterior-horn damage;
  • peripheral neuropathy;
  • autonomic disease;
  • muscle injury;
  • vascular injury;
  • cardiac disease;
  • endocrine dysfunction;
  • GI dysmotility;
  • autoimmunity.

If virus persists or remains uncertain:

RAPID PERSISTENT-EV BLOOD PANEL

↓

ULTRASENSITIVE RNA / PBMC RNA / ANTIGEN / PROTEIN / IMMUNE SIGNATURE

↓

TARGETED BIOPSY IF REQUIRED

↓

RNA + PROTEIN + LOCALISATION + SEQUENCE

↓

PERSISTENT VIRUS

↓

COMBINATION ANTIVIRAL THERAPY

↓

VIRAL-LOAD MONITORING

↓

RESISTANCE TESTING

↓

SALVAGE THERAPY IF REQUIRED

↓

HUMORAL IMMUNE REPLACEMENT WHERE DEFICIENT

↓

REASSESS.

COMPLETE BLOOD-VOLUME / CEREBRAL-PERFUSION PIPELINE

ENTEROVIRAL CNS / AUTONOMIC / VASCULAR DISEASE

↓

DIRECT OBJECTIVE BLOOD-VOLUME MEASUREMENT

TOTAL BLOOD VOLUME

PLASMA VOLUME

RED-CELL VOLUME

↓

AUTONOMIC / HAEMODYNAMIC TESTING

SUPINE / UPRIGHT BP

HEART RATE

ACTIVE STAND

TILT

BEAT-TO-BEAT BP

VENOUS POOLING

CARDIAC FILLING

↓

CEREBRAL-PERFUSION TESTING

BRAIN-PERFUSION SPECT

↓

SEGAMI OASIS / NEUROGAM QUANTITATIVE REGIONAL ANALYSIS

ASL-MRI

TRANSCRANIAL / ORTHOSTATIC CEREBRAL-FLOW MEASURES

↓

CORRELATE:

BLOOD-VOLUME DEFICIT

with

AUTONOMIC ABNORMALITIES

with

REGIONAL CEREBRAL HYPOPERFUSION

with

NEUROLOGICAL FUNCTION

with

BRAINSTEM / ENDOTHELIAL / INFLAMMATORY MARKERS

↓

TREAT THE IDENTIFIED MECHANISM

↓

REPEAT BLOOD-VOLUME + AUTONOMIC + PERFUSION MEASUREMENTS.

AUTOIMMUNE TREATMENT PIPELINE

POST-INFECTIOUS / PERSISTENCE-ASSOCIATED AUTOIMMUNITY

↓

IDENTIFY THE IMMUNE TARGET

↓

DETECT AUTOANTIBODY

↓

FUNCTIONALLY VALIDATE PATHOGENICITY

↓

RAPID REMOVAL WHERE CLINICALLY NECESSARY

PLASMA EXCHANGE / IMMUNOADSORPTION

↓

PREVENT REBOUND

B-CELL / PLASMA-CELL / OTHER PRECISION IMMUNOTHERAPY

↓

RESTORE ANTIGEN-SPECIFIC TOLERANCE

↓

REPAIR NERVE / MUSCLE / VASCULAR / ORGAN DAMAGE.

COMPLETE NUTRITION PATHWAY

ENTEROVIRAL CNS / BRAINSTEM / BULBAR / AUTONOMIC / ENTERIC DISEASE

↓

IS SWALLOWING SAFE AND NUTRITION ADEQUATE?

YES

oral nutrition with monitoring.

NO / INADEQUATE

↓

ENTERAL NUTRITION

NG

or

NJ

or

PEG / RIG

or

GJ / PEG-J

or

DIRECT JEJUNOSTOMY

according to:

  • swallow safety;
  • aspiration risk;
  • gastric function;
  • intestinal function;
  • expected duration.

If severe:

  • gastroparesis;
  • intestinal paresis;
  • paralytic ileus;
  • chronic pseudo-obstruction;
  • intestinal failure

prevents adequate GI nutrition:

↓

PARENTERAL NUTRITION / TPN

↓

MAINTAIN NUTRITION WHILE UNDERLYING NEUROLOGICAL / AUTONOMIC / GI DISEASE IS INVESTIGATED AND TREATED.

REGENERATIVE PIPELINE

STOP ACTIVE VIRAL INJURY

↓

CONTROL PATHOGENIC IMMUNITY

↓

PROTECT SURVIVING CELLS

↓

REGENERATE AXONS

↓

REMYELINATE

↓

REINNERVATE MUSCLE

↓

RESTORE AUTONOMIC NETWORKS

↓

RESTORE MICROVASCULAR SUPPORT

↓

RESTORE CEREBRAL PERFUSION

↓

REPAIR HEART

↓

REPAIR GI / ENTERIC SYSTEM

↓

REPAIR PERIPHERAL NERVE

↓

REPAIR CNS.

COMPLETE MULTISYSTEM ENTEROVIRUS MAP

ENTEROVIRUS

↓

ENTRY

OROPHARYNX • RESPIRATORY TRACT • GI TRACT

↓

CELLULAR COMPARTMENTS

EPITHELIAL • ENDOTHELIAL • FIBROBLAST • LEUKOCYTE

↓

LYMPHOID / BLOOD PHASE

↓

CENTRAL / PERIPHERAL NERVOUS SYSTEM

MOTOR COMPARTMENT

MOTOR CORTEX → CORTICOSPINAL PATHWAY → BRAINSTEM → SPINAL CORD → ANTERIOR HORN → MOTOR ROOT → BRACHIAL PLEXUS → PERIPHERAL MOTOR NERVE → MUSCLE

SENSORY COMPARTMENT

DRG → SENSORY NERVE → SPINAL SENSORY PATHWAYS → THALAMUS → CORTEX

AUDITORY / VESTIBULAR COMPARTMENT

LABYRINTH → VIII NERVE → BRAINSTEM NUCLEI → CENTRAL AUDITORY / VESTIBULAR PATHWAYS

HOMEOSTATIC / AUTONOMIC COMPARTMENT

HYPOTHALAMUS → BRAINSTEM AUTONOMIC NUCLEI → AUTONOMIC GANGLIA → PERIPHERAL AUTONOMIC NERVES → ENTERIC NERVOUS SYSTEM

↓

MULTI-ORGAN DISEASE

RESPIRATORY

rhinosinusitis • pharyngitis • bronchitis • bronchiolitis • pleurisy • pneumonia

GI

vomiting • diarrhoea • gastritis • terminal ileitis • colitis • mesenteric adenitis • hepatitis • GERD • functional dyspepsia • gastroparesis • paralytic ileus • chronic intestinal pseudo-obstruction

PANCREAS

pancreatitis • pancreatic persistence • beta-cell stress • Type 1 diabetes research

HEART

myocarditis • pericarditis • myopericarditis • arrhythmia • persistent myocardial EV • dilated cardiomyopathy

MUSCLE

acute myositis • inflammatory-myopathy mimic • rhabdomyolysis • pleurodynia • abnormal muscle fatigability • paresis • muscle wasting

ENDOCRINE

primary thyroid failure • Hashimoto thyroiditis • thyroid atrophy • subacute thyroiditis • low-T3 syndrome • altered cortisol stress response • circadian-rhythm disruption

IMMUNE / AUTOIMMUNE

GBS • Miller Fisher syndrome • autoimmune neuropathy • myasthenia gravis • autoimmune gastritis • pernicious anaemia • autoimmune haemolytic anaemia • connective-tissue autoimmunity

VASCULAR

endothelial inflammation • Raynaud’s • microvascular disease • BBB/BSCB disease • perivascular cuffing • vasa-nervorum pathology

RHEUMATOLOGICAL

arthralgia • arthritis • seronegative polyarthritis • palindromic rheumatism research • mixed connective-tissue disease research

PAIN

small-fibre neuropathy • neuropathic pain • CRPS-like disease • fibromyalgia comparator research

SENSORY

photophobia • hyperacusis • tinnitus • labyrinthitis • vertigo • hearing loss • migraine research

SKIN / ORAL / EYE

HFMD • herpangina • enanthem • mouth/tongue ulcers • vesicles • maculopapular rash • petechiae • urticaria • vasculitic lesions • haemorrhagic conjunctivitis

GENITOURINARY / REPRODUCTIVE

epididymitis • orchitis • prostatitis • salpingitis research • endometriosis exploratory research

SYSTEMIC / NEONATAL

adult sepsis-like disease • neonatal sepsis-like disease • shock • pneumonia • hepatitis • coagulopathy • myocarditis • meningoencephalitis • multi-organ failure.

INVESTIGATIONAL RULE FOR EVERY PROPOSED ASSOCIATION

For every proposed disease relationship ask:

WHICH ENTEROVIRUS?

WHICH SPECIES?

WHICH SEROTYPE?

WHICH GENOME?

WHICH CELL?

WHICH TISSUE?

WHICH ANATOMICAL COMPARTMENT?

DIRECT INFECTION OR POST-INFECTIOUS IMMUNITY?

ACTIVE REPLICATION OR RESIDUAL ANTIGEN?

ACUTE OR PERSISTENT?

VIRAL, AUTOIMMUNE, VASCULAR, AUTONOMIC, ENDOCRINE, METABOLIC OR MIXED?

DID THE VIRUS PRECEDE THE DISEASE?

CAN VIRAL MATERIAL BE LOCALISED IN THE AFFECTED TISSUE?

IS THE FINDING REPRODUCIBLE?

ARE APPROPRIATE CONTROLS INCLUDED?

DOES ANTIVIRAL TREATMENT CHANGE THE DISEASE?

DOES TARGETED ANTI-INFLAMMATORY TREATMENT CHANGE THE DISEASE?

DOES IMMUNOMODULATION CHANGE THE DISEASE?

DOES AUTOANTIBODY REMOVAL CHANGE THE DISEASE?

CAN THE DAMAGED NERVOUS SYSTEM OR ORGAN BE REPAIRED?

2026–2036 IMPLEMENTATION ROADMAP

YEARS 1–2 — CATCH IT

Establish:

  • 100% ring-fenced programme funding;
  • Historical/Ramsay-M.E. ascertainment;
  • urgent acute EV pathways;
  • same-day multi-compartment sampling;
  • rapid pan-EV tests;
  • rapid serotyping;
  • rapid viral-load assays;
  • reference laboratories;
  • AFM pathways;
  • EV-A71 surveillance;
  • EV-D68 surveillance;
  • neonatal EV sepsis surveillance;
  • GBS/MFS surveillance;
  • specialist autonomic services;
  • direct blood-volume protocols;
  • Segami Oasis/NeuroGam SPECT protocols;
  • ASL/perfusion protocols;
  • emergency dysphagia pathways;
  • enteral/TPN pathways;
  • tissue-bank infrastructure;
  • international registry.

YEARS 2–3 — IDENTIFY AND TYPE IT

Deliver:

  • rapid VP1;
  • WGS;
  • persistent-EV blood-test development;
  • tissue persistence diagnostics;
  • chronic serotyping;
  • viral-reservoir mapping;
  • lymphoid research;
  • root/brachial-plexus mapping;
  • endocrine cohorts;
  • pancreatic/T1D cohorts;
  • autoimmune cohorts;
  • direct blood-volume/perfusion correlation studies.

YEARS 3–5 — MAP IT

Map:

  • brain;
  • brainstem;
  • spinal cord;
  • anterior horn;
  • motor roots;
  • brachial plexus;
  • DRG;
  • small fibres;
  • large fibres;
  • autonomic fibres;
  • auditory/vestibular pathways;
  • cerebral perfusion;
  • blood volume;
  • GI/enteric nervous system;
  • skeletal muscle;
  • myocardium;
  • vasculature;
  • pancreas;
  • thyroid;
  • lymphoid tissue;
  • immune phenotypes;
  • autoantibodies;
  • rheumatological phenotypes;
  • mast-cell/intolerance phenotypes.

YEARS 4–7 — DEVELOP TREATMENT

Develop:

  • entry inhibitors;
  • capsid inhibitors;
  • uncoating inhibitors;
  • 2A inhibitors;
  • 2C inhibitors;
  • 3C protease inhibitors;
  • 3D polymerase inhibitors;
  • host-factor antivirals;
  • broad-spectrum enterovirus drugs;
  • combination antiviral regimens;
  • viral-load-guided treatment;
  • resistance testing;
  • salvage therapy;
  • monoclonal antibodies;
  • RNA-targeting therapeutics;
  • acute-neuroinflammation drugs;
  • chronic-neuroinflammation drugs;
  • antiviral + anti-inflammatory combinations;
  • IVIG trials;
  • IVIG/SCIG replacement studies;
  • precision immunomodulation;
  • B-cell treatment where justified;
  • plasma-cell treatment where justified;
  • complement treatment;
  • plasmapheresis;
  • immunoadsorption;
  • antigen-specific immunoadsorption;
  • rintatolimod trials;
  • low-blood-volume treatment;
  • dysautonomia treatment;
  • cerebral-perfusion restoration;
  • GI-motility treatment;
  • vascular treatment;
  • objectively confirmed mast-cell treatment.

YEARS 5–10 — REPAIR AND PREVENT

Develop:

  • CNS repair;
  • anterior-horn repair;
  • motor-neuron preservation;
  • motor-unit reinnervation;
  • brachial-plexus reconstruction where appropriate;
  • small-fibre regeneration;
  • large-fibre regeneration;
  • remyelination;
  • autonomic-nerve regeneration;
  • stem-cell platforms;
  • iPSC disease models;
  • Schwann-cell strategies;
  • oligodendrocyte strategies;
  • endothelial/pericyte repair;
  • cardiac regeneration;
  • cerebral-perfusion restoration;
  • specialist nutrition and intestinal-failure services;
  • specialist enterovirus centres;
  • multivalent vaccines.

FINAL PRINCIPLES

ENTEROVIRUSES CHANGE.

SEROTYPES CHANGE.

EPIDEMICS MOVE.

TISSUE TROPISM DIFFERS.

CLINICAL PRESENTATIONS DIFFER.

THE REQUIREMENT FOR RAPID VIROLOGY DOES NOT.

THE REQUIREMENT FOR RAPID BLOOD TEST DEVELOPMENT DOES NOT.

THE REQUIREMENT FOR OBJECTIVE BLOOD-VOLUME TESTING DOES NOT.

THE REQUIREMENT FOR OBJECTIVE CEREBRAL-PERFUSION MEASUREMENT DOES NOT.

THE REQUIREMENT FOR ANTIVIRAL DEVELOPMENT DOES NOT.

THE REQUIREMENT TO DISTINGUISH ACTIVE VIRUS FROM IMMUNE-MEDIATED DAMAGE DOES NOT.

THE REQUIREMENT TO REPAIR WHAT HAS BEEN DAMAGED DOES NOT.

CATCH IT.

SAMPLE IT.

TEST IT RAPIDLY.

TYPE IT RAPIDLY.

QUANTIFY IT.

SEQUENCE IT.

LOCALISE IT.

MAP IT.

MEASURE BLOOD VOLUME DIRECTLY.

MEASURE CEREBRAL PERFUSION DIRECTLY.

USE SEGAMI OASIS / NEUROGAM TO QUANTIFY REGIONAL SPECT PERFUSION WHERE APPROPRIATE.

CORRELATE PERFUSION WITH BLOOD VOLUME AND AUTONOMIC FUNCTION.

TREAT IT.

FIND IT IF IT PERSISTS.

DEVELOP MULTIPLE ANTIVIRAL CLASSES.

USE COMBINATION THERAPY WHERE THE BIOLOGY SUPPORTS IT.

TEST FOR RESISTANCE.

DEVELOP SALVAGE THERAPY.

RESTORE ANTIVIRAL IMMUNITY WHERE DEFICIENT.

IDENTIFY PATHOGENIC AUTOANTIBODIES.

FUNCTIONALLY VALIDATE THEM.

REMOVE THEM WHERE NECESSARY.

PREVENT THEIR REBOUND.

RESTORE IMMUNE TOLERANCE.

CONTROL DAMAGING INFLAMMATION.

MAINTAIN NUTRITION.

RESTORE BLOOD VOLUME WHERE OBJECTIVELY LOW.

RESTORE CEREBRAL PERFUSION WHERE OBJECTIVELY IMPAIRED.

REGENERATE NERVES.

REMYELINATE.

REINNERVATE MUSCLE.

REPAIR THE HEART.

REPAIR THE VASCULATURE.

REPAIR THE ENTERIC NERVOUS SYSTEM.

REPAIR THE CNS.

PREVENT THE NEXT CASE.

All funding allocated under this proposed roadmap should remain ring-fenced for Historical/Ramsay Myalgic Encephalomyelitis / Enteroviral Encephalomyelitis and the directly related enteroviral disease programme defined above, including rapid diagnostics, chronic-infection diagnostics, virology, genomics, antiviral development, immunology, autoantibody treatment, blood-volume research, cerebral-perfusion research, regenerative medicine, rehabilitation, education, surveillance and prevention.


----------------------------------------------------

Overlap of "Abortive Poliomyelitis" onset symptoms and "Encephalitis" in RED and "Myalgic Encephalomyelitis" (also known as Enteroviral Encephalomyelitis) M.E. in GREEN. 

The YELLOW area is a seperate concept coined "SEID" which rejects both "M.E." and "CFS" as names; to reflect something else, entirely. 

"Myalgic Encephalomyelitis" (also known as Enteroviral Encephalomyelitis) M.E. and Enteroviral Encephalitis is "EXCLUDED" from the SEID algorithm as diagnosable "neurological diseases" and are not the same thing as an ill-defined "diagnosis of exclusion" *post-acute* fatigue syndrome. 






A ROADMAP FOR 'SEID' (erroneously labelled as "ME/CFS" currently) 

(which is neither the "original" Lake Tahoe "CFS" [Abortive Polio onset symptoms; mixed with "Sudden Onset" Encephalitis overlap] and "Sudden Onset" Royal Free "M.E." (also known as Enteroviral Encephalomyelitis) - THEY WOULD NOT BE THE SAME as "SEID", and are actually 'EXCLUDED' from the "SEID" algorithm. Both of these "sudden onset' neurological diagnoses, would "require" emergency inpatient medical care, and related services)










Comments

Post a Comment

Popular posts from this blog

Myalgic Encephalomyelitis or What? (2025 Edition) - Comprehensive Symptom and Comorbidity Overview by Larrin Carney

Image
Epidemic Myalgic Encephalomyelitis   ( M.E. )  (also known as 01.  Enteroviral Encephalomyelitis )  / 02.  Poliomyelitis-like Syndrome ) - Comprehensive Symptom and Comorbidity Overview Abstract Since 1934 , Myalgic Encephalomyelitis (M.E.) (also known as Enteroviral Encephalomyelitis )  has been increasingly reported from socially developed countries and temperate regions of the world. Endemic prevalence alternates with periodic epidemics, showing a curious predilection for female staff of health care and teaching institutions. Maximum incidence in both sexes occurs in the third decade. M.E. is a multi-system disease including nervous, cardiovascular, endocrine and other involvement, distinguished by severe muscle fatigue following trivial exertion . Other characteristics include high morbidity, a prolonged relapsing course and variation in intensity of symptoms within and between epis...
Read more

'ME/CFS' or 'CFS/ME' do not exist!!!! (Part 2)

Image
What is CFS ? (According to Action for M.E. - who are still 'pretending' M.E. is the same as misdiagnosed "CFS" patients, who are different patient cohorts) 'Chronic Fatigue Syndrome' criteria, section (with mention of 'M.E.' from time to time) The CFS Misdiagnosis Trap - A label without answers. A dead end for patients.  "CFS" is a chronic, fluctuating disease that effects an estimated 1.35m in the UK, causing symptoms such as Post-Exertional Malaise (PEM), crushing "FATIGUE", brain fog (Cognitive Impairment), and sleep problems (Unrefreshing Sleep). (This is a discription of the "CFS" (SEID) Algorithm and 'NOT' Myalgic Encephalomyelitis (also known as "Enteroviral Encephalomyelitis" which is closer to 2011 ICC, 1986 & 1988 Ramsay and 2007 & 2016 Nightingale Research Foundation Definitions, which indicates an "acute onset" illness, medical investigati...
Read more

Letters to Andy Burnham MP (Health Secretary) about Sophia Mirza and Myalgic Encephalomyelitis (M.E.) from Criona Wilson

Image
ORIGINAL LETTER TO ANDY BURNHAM Mr. Andy Burnham Secretary of State for Health House of Commons London SW1A 0AA 1st July 2009 Dear Mr Burnham, In 2005, my daughter Sophia Mirza died after doctors refused to recognise her M.E. as a serious physical disease and instead had her "sectioned" in a mental hospital because she insisted that M.E. was a physical disease and not a mental illness. She never recovered from her incarceration and later died. Examination of her spinal cord after death confirmed she was physically ill and this was reflected by the Coroner at her inquest in 2006. (For more information see www.sophiaandme.org.uk ⁠). Myalgic Encephalomyelitis (M.E.) affects over 240,000 people in the UK and a quarter of these people are so badly affected that they are housebound or bed bound. The illness is neurological; it affects all systems of the body and commonly affects many young people. M.E. has been classified by the World Health Organisation (WHO) as a phys...
Read more