Acute Flaccid Myelitis

Neurological Disorder MONDO:0100115 Pathograph 21 Show in embeddings browser Myelitis Acute disease Central nervous system disorder

Acute flaccid myelitis (AFM) is a rare, acute, polio-like neurologic syndrome, mainly reported in children, with rapid flaccid limb weakness and spinal cord gray-matter involvement. Most cases follow a febrile or respiratory prodrome. The clinical syndrome localizes predominantly to lower motor neurons in the anterior horn of the spinal cord, can involve cranial, bulbar, axial, and respiratory muscles, and is strongly associated epidemiologically with non-polio enteroviruses, especially enterovirus D68.

Ask OpenScientist

Ask a research question about Acute Flaccid Myelitis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

📘

Definitions

Clinical and radiologic AFM syndrome

AFM is defined clinically by acute flaccid limb weakness with objective evidence of spinal cord gray-matter involvement, typically by MRI, and/or supporting cerebrospinal-fluid inflammation after exclusion of mimics such as Guillain-Barre syndrome, spinal cord infarction, poliomyelitis, and transverse myelitis.

CASE_DEFINITION

Core AFM features

Core clinical characteristics

acute flaccid limb weakness Rapid onset limb weakness with lower motor neuron features.
spinal cord gray matter lesion MRI lesion centered in spinal cord gray matter, especially the anterior horns.
CSF pleocytosis Supportive inflammatory cerebrospinal-fluid finding in probable or definite AFM criteria.

Show evidence (1 reference)

PMID:31409689 SUPPORT Human Clinical

"Classification criteria for a confirmed AFM case are acute flaccid limb weakness and magnetic resonance imaging evidence of a predominantly gray matter lesion that spans at least one spinal segment"

This reproduces the surveillance definition for confirmed AFM and directly supports the two required core criteria.

Show evidence (2 references)

PMID:27422805 SUPPORT Human Clinical

"acute flaccid limb weakness with spinal cord gray matter lesions"

The US case review directly supports the core clinical-radiologic definition used here.

PMID:33357469 SUPPORT Human Clinical

"no single sensitive and specific test for AFM"

The Lancet review supports modeling AFM as a syndromic diagnosis requiring integrated clinical, MRI, CSF, and exclusionary evidence.

◈

Mechanistic Hypotheses

EV-D68 Direct Neuroinvasion Model

ev_d68_direct_neuroinvasion_model CANONICAL

Evidence balance 2 support

In the best-supported model for epidemic AFM, EV-D68 respiratory infection is followed rarely by CNS access, receptor-mediated infection of spinal neural cells, and anterior-horn motor-neuron injury. Epidemiologic and human CSF evidence support the association, while mouse and organoid systems show that contemporary EV-D68 strains can infect neural tissue and cause paralytic myelitis. The model does not imply virologic confirmation in every patient.

Pathograph links

Non-polio Enterovirus Respiratory Infection -> Prodromal respiratory tract infection INDIRECT KNOWN INTERMEDIATES Respiratory enterovirus infection commonly produces the febrile or respiratory prodrome that precedes neurologic weakness.

Non-polio Enterovirus Respiratory Infection -> MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry INDIRECT UNKNOWN INTERMEDIATES Respiratory infection precedes rare CNS access and neural-cell entry, but the route of spread and other intervening determinants are not established.

MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry -> Spinal Neural Cell Tropism and Infection DIRECT Receptor-dependent cell entry permits productive EV-D68 infection in susceptible neural cells.

Spinal Neural Cell Tropism and Infection -> Spinal Gray Matter Inflammation and Motor Neuron Injury INDIRECT KNOWN INTERMEDIATES Neural infection can precede motor-neuron injury through direct viral effects and/or secondary inflammatory injury; their relative contribution in human AFM remains unresolved.

Show evidence (2 references)

PMID:28231269 SUPPORT Model Organism

"Virus isolated from spinal cords of infected mice transmitted disease when injected into naïve mice, fulfilling Koch's postulates in this model."

Experimental transmission establishes direct causation in the mouse model, while the qualification "in this model" prevents overextension to humans.

PMID:33357469 SUPPORT Human Clinical

"the disease appears to be caused by non-polio enterovirus infection"

The clinical review identifies non-polio enterovirus infection as the leading human etiologic model.

Secondary Immune-Mediated Neural Injury Model

secondary_immune_mediated_injury_model EMERGING

Evidence balance 1 support

Direct neural infection may initiate AFM without being sufficient to cause the full motor-neuron injury. Persistent productive infection with little cytopathic effect in human spinal-cord organoids suggests that host immune responses or other secondary injury mechanisms may contribute to neuronal loss.

Pathograph links

Spinal Gray Matter Inflammation and Motor Neuron Injury -> CSF pleocytosis INDIRECT KNOWN INTERMEDIATES CNS inflammation can increase leukocytes in CSF, although pleocytosis is supportive rather than required or disease-specific.

Show evidence (1 reference)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"EV-D68 infection is not the sole mediator of neuronal cell death in the spinal cord in those with AFM and that secondary injury from the immune response likely contributes to pathogenesis."

The human organoid study explicitly proposes secondary immune injury after observing prolonged productive infection without appreciable cytopathy.

Discussions and Knowledge Gaps

What proportion of human AFM is directly caused by EV-D68 neuroinvasion, and which tests can establish that cause in an individual patient?

KNOWLEDGE GAP OPEN afm_ev_d68_human_causation_boundary

Attached to

infectious_agent#Enterovirus D68 pathophysiology#Non-polio Enterovirus Respiratory Infection

Outbreak timing, respiratory detections, CSF antibodies, animal causation, and human-organoid infection form a coherent causal case. However, viral RNA is rarely detected in human CSF, case-control estimates are heterogeneous, and AFM is a syndrome with other infectious and noninfectious mimics. The graph therefore treats EV-D68 neuroinvasion as the canonical model for epidemic disease without assigning it to every case.

Posed 2026-07-20T00:00:00Z

Show evidence (2 references)

PMID:42066114 SUPPORT Human Clinical

"Across 98 studies, the pooled odds ratio (OR) was 1.39 (95% CI 1.14-1.69), with high heterogeneity (I2 = 98.9%; prediction interval 0.24-8.15)."

The high heterogeneity quantifies uncertainty in human association estimates.

PMID:31409689 SUPPORT Human Clinical

"supports the plausibility of a link between EV infection and AFM that warrants further investigation"

The CSF-antibody study explicitly frames its evidence as plausibility, not proof.

Why do large EV-D68 respiratory waves not consistently produce parallel AFM peaks, and what host or viral determinants govern the rare paralytic outcome?

KNOWLEDGE GAP OPEN afm_respiratory_wave_paralysis_mismatch

Attached to

epidemiology#United States surveillance since the 2018 peak environmental#EV-D68 respiratory circulation and wastewater seasonality

AFM counts remained low during the 2022 US EV-D68 circulation increase. Prospective linked respiratory, wastewater, genomic, host-immunologic, and neurologic surveillance is needed to distinguish viral genotype, prior immunity, ascertainment, and host susceptibility effects.

Posed 2026-07-20T00:00:00Z

Show evidence (1 reference)

PMID:38300829 SUPPORT Human Clinical

"It is unclear why EV-D68 circulation in 2022 was not associated with an increase in AFM cases"

The national surveillance report states the mismatch directly.

Which immune and developmental features must be added to organoid and mouse systems to reproduce human AFM motor-neuron loss and recovery?

HUMAN MODEL MISMATCH OPEN afm_organoid_mouse_translation_limit

Attached to

experimental_models#Human iPSC-derived spinal cord organoids infected with EV-D68 animal_models#mouse

Organoids show prolonged productive infection without appreciable cytopathy and lack a complete immune compartment. Mice are not native EV-D68 hosts and commonly require neonatal or modified conditions. These systems prove mechanistic capabilities but cannot determine the human balance between direct infection and immune-mediated injury.

Posed 2026-07-20T00:00:00Z

Show evidence (1 reference)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"Mice are not native hosts for EV-D68, and thus, existing mouse models use immunosuppressed or neonatal mice, mouse-adapted viruses, or intracranial inoculations."

The organoid paper directly states key limitations of animal translation.

⚙

Pathophysiology

Non-polio Enterovirus Respiratory Infection

AFM most often occurs after a respiratory or febrile illness. EV-D68 is the leading epidemic-associated virus. Only a very small fraction of respiratory infections are followed by AFM, and the route and determinants that permit subsequent CNS access in children remain unresolved.

EV-D68 Direct Neuroinvasion Model

response to virus GO:0009615 ↑ INCREASED

respiratory system UBERON:0001004 central nervous system UBERON:0001017

Downstream

Prodromal respiratory tract infection Respiratory enterovirus infection commonly produces the febrile or respiratory prodrome that precedes neurologic weakness.

MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry Respiratory infection precedes rare CNS access and neural-cell entry, but the route of spread and other intervening determinants are not established.

Show evidence (2 references)

PMID:33357469 SUPPORT Human Clinical

"the disease appears to be caused by non-polio enterovirus infection"

This clinical synthesis supports the enterovirus model while appropriately using probabilistic wording.

PMID:31409689 SUPPORT Human Clinical

"The cause of AFM remains elusive. An infectious agent is only rarely detected in cerebrospinal fluid (CSF)."

Direct human etiologic confirmation is uncommon and the graph therefore does not represent neuroinvasion as proven in every case.

MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry

MFSD6 is a directly demonstrated EV-D68 entry receptor in respiratory and neural primary cells. ICAM5 is a proposed neuron-specific receptor and is retained as complementary, lower-tier evidence rather than treated as a universal AFM receptor mechanism.

EV-D68 Direct Neuroinvasion Model

MFSD6 hgnc:24711 ICAM5 hgnc:5348

symbiont entry into host cell GO:0046718 ↑ INCREASED

Downstream

Spinal Neural Cell Tropism and Infection Receptor-dependent cell entry permits productive EV-D68 infection in susceptible neural cells.

Show evidence (2 references)

PMID:40132641 SUPPORT In Vitro

"Knockout of MFSD6 expression abrogated EV-D68 infection in cell lines and primary cells corresponding to respiratory and neural cells."

Genetic loss-of-function and primary-cell experiments directly support MFSD6-dependent entry.

PMID:41467840 SUPPORT Other

"ICAM-5) as a neuron-specific receptor that provides a molecular explanation for neurotropism in AFM."

A receptor-usage review supports ICAM5 as a neuron-specific alternative, but this is weaker evidence than the MFSD6 perturbation experiments.

Spinal Neural Cell Tropism and Infection

Contemporary EV-D68 strains productively infect human spinal-cord organoids. Tropism differs by strain across neurons, cycling astrocytes, and oligodendrocyte precursor cells, indicating that neural susceptibility is neither uniform nor explained by motor neurons alone.

EV-D68 Direct Neuroinvasion Model Secondary Immune-Mediated Neural Injury Model

motor neuron CL:0000100 astrocyte CL:0000127 oligodendrocyte precursor cell CL:0002453

spinal cord UBERON:0002240

Experimental models

Human iPSC-derived spinal cord organoids infected with EV-D68 ORGANOID Tests whether historical and contemporary EV-D68 strains productively infect human spinal neural populations.

Downstream

Spinal Gray Matter Inflammation and Motor Neuron Injury Neural infection can precede motor-neuron injury through direct viral effects and/or secondary inflammatory injury; their relative contribution in human AFM remains unresolved.

Show evidence (2 references)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"productively infected with contemporary strains, but not a historic strain, of EV-D68"

Productive infection in human spinal-cord organoids establishes direct human-cell neural tropism and a strain effect.

DOI:10.3389/fmicb.2025.1698639 SUPPORT In Vitro

"distinct viral tropism and host transcriptional responses"

Single-cell profiling supports strain- and cell-type-specific tropism.

Spinal Gray Matter Inflammation and Motor Neuron Injury

AFM injury is centered on spinal gray matter and anterior-horn motor neurons. Cranial motor nuclei can also be involved, accounting for facial, bulbar, and respiratory manifestations that cannot be attributed to spinal anterior horns alone.

Secondary Immune-Mediated Neural Injury Model

anterior horn motor neuron CL:2000048

inflammatory response GO:0006954 ↑ INCREASED

ventral horn of spinal cord UBERON:0002257 brainstem UBERON:0002298

Experimental models

Human iPSC-derived spinal cord organoids infected with EV-D68 ORGANOID Separates productive viral infection from overt cytopathic injury and motivates testing secondary immune-mediated damage.

Downstream

Spinal cord gray matter lesion Gray-matter injury is visualized as the characteristic spinal-cord MRI abnormality.

CSF pleocytosis CNS inflammation can increase leukocytes in CSF, although pleocytosis is supportive rather than required or disease-specific.

Segmental and Cranial Lower Motor Neuron Dysfunction Loss or dysfunction of spinal and cranial motor neurons produces the characteristic lower-motor-neuron syndrome.

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"The primary site of injury in AFM is the anterior horn cells of the spinal cord"

The clinical review identifies the principal anatomic lesion.

Segmental and Cranial Lower Motor Neuron Dysfunction

Dysfunction of segmental anterior-horn and cranial motor systems produces rapid flaccid weakness, depressed reflexes, asymmetry, and, when brainstem or respiratory motor pools are affected, facial, bulbar, or ventilatory impairment.

motor neuron CL:0000100

ventral horn of spinal cord UBERON:0002257 brainstem UBERON:0002298

Downstream

Acute flaccid paralysis Motor-neuron dysfunction produces acute flaccid paralysis.

Acute limb weakness Segmental motor-neuron dysfunction produces abrupt limb weakness.

Asymmetric limb weakness Patchy segmental motor-pool injury often produces asymmetric weakness.

Areflexia Lower-motor-neuron dysfunction interrupts the reflex arc.

Cranial nerve palsy Cranial motor-system involvement can produce cranial neuropathies.

Facial weakness Facial motor involvement can cause weakness of facial musculature.

Bulbar palsy Brainstem motor involvement can impair bulbar function.

Respiratory insufficiency due to muscle weakness Respiratory motor-pool involvement can cause ventilatory failure.

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."

This defines the motor distribution beyond limb weakness.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Head and Neck 1

Facial weakness Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."

The review lists facial muscle involvement in the broader set of AFM muscle groups that can be affected.

Limbs 2

Acute limb weakness Limb muscle weakness HP:0003690

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"acute-onset flaccid limb weakness"

The review identifies acute flaccid limb weakness as a defining feature.

Asymmetric limb weakness FREQUENT Limb muscle weakness HP:0003690

Show evidence (1 reference)

PMID:34747551 SUPPORT Human Clinical

"asymmetric limb weakness (58% vs. 0%, p < 0.001)"

Fifty-eight percent of the AFM cohort had asymmetric weakness, supporting the frequent band and its value against GBS.

Musculoskeletal 1

Respiratory insufficiency due to muscle weakness OCCASIONAL HP:0002747

Show evidence (1 reference)

PMID:39657203 SUPPORT Human Clinical

"Eight patients (21.6%) had respiratory failure during the index hospitalization."

Eight of 37 children had respiratory failure, directly supporting the occasional frequency band in this cohort.

Nervous System 3

Acute flaccid paralysis HP:0003470

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"acute flaccid paralysis"

Acute flaccid paralysis is part of the core clinical description of AFM.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:39163469 SUPPORT Human Clinical

"decreased or absent reflexes"

The StatPearls clinical summary supports decreased or absent reflexes as a classic AFM finding.

Cranial nerve palsy Cranial nerve paralysis HP:0006824

Show evidence (1 reference)

PMID:31014167 SUPPORT Human Clinical

"with cranial neuropathy"

The EV-D68-associated AFM review describes cranial neuropathy among common presenting features.

Other 4

Prodromal respiratory tract infection HP:0011947

Temporal: ACUTE

Show evidence (1 reference)

PMID:39163469 SUPPORT Human Clinical

"upper respiratory tract infection"

The clinical summary identifies a preceding upper respiratory infection; no frequency band is assigned because the available quantitative endpoint pooled respiratory and gastrointestinal prodromes.

Spinal cord gray matter lesion VERY_FREQUENT Spinal cord lesion HP:0100561

Show evidence (1 reference)

PMID:26720027 SUPPORT Human Clinical

"Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging"

Fifty-six of 59 cases had the MRI abnormality, supporting the very-frequent band.

CSF pleocytosis FREQUENT HP:0012229

Show evidence (1 reference)

PMID:26720027 SUPPORT Human Clinical

"43 patients had cerebrospinal fluid pleocytosis"

Forty-three of 59 cases had CSF pleocytosis, supporting the frequent band.

Bulbar palsy HP:0001283

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."

The review lists bulbar involvement in the broader set of AFM muscle groups that can be affected.

🗃️

External Assertions

Orphanet acute flaccid myelitis record

Orphanet structured disease record ORPHA:623801

Orphanet's ORPHA:623801 structured record for acute flaccid myelitis provides the rare-disease identifier, exact MONDO cross-reference, narrower ICD-10 mapping, MeSH and UMLS cross-references, broad onset categories, and international incidence annotations used to cross-check this entry.

Show evidence (2 references)

ORPHA:623801 SUPPORT Other

"MONDO:0100115 | Exact"

Orphanet maps ORPHA:623801 exactly to the MONDO disease identifier used by this entry.

ORPHA:623801 SUPPORT Other

"ICD-10:G04.8 | Narrower"

The Orphanet cross-reference table records a narrower ICD-10 mapping for AFM.

💊

Medical Actions

Acute supportive care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Acute management is primarily supportive and includes close monitoring for bulbar and respiratory muscle involvement, intensive-care support when needed, pain control, prevention of complications, and multidisciplinary neurologic and infectious-disease evaluation.

Target Phenotypes: Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (1 reference)

PMID:33357469 SUPPORT Human Clinical

"guide diagnosis, management, and rehabilitation"

The Lancet review supports management and rehabilitation as central AFM care domains.

Mechanical ventilatory support

Action: mechanical ventilation Ontology label: Mechanical Ventilation NCIT:C70909

Respiratory muscle weakness or bulbar dysfunction can require intubation, invasive mechanical ventilation, or other airway and respiratory support.

Target Phenotypes: Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (1 reference)

PMID:39163469 SUPPORT Human Clinical

"requires intubation and mechanical ventilation"

The current clinical summary supports ventilatory support for severe AFM respiratory insufficiency.

Physical therapy and rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Long-term care relies on early, intensive, and individualized rehabilitation, including physical therapy, occupational therapy, bracing, orthopedic monitoring, and functional support for residual motor deficits.

Target Phenotypes: Limb muscle weakness HP:0003690

Show evidence (1 reference)

PMID:33357469 SUPPORT Human Clinical

"unique long-term rehabilitation needs"

The Lancet review directly supports rehabilitation as a core AFM management need.

Transcutaneous spinal cord stimulation with gait training

Action: spinal cord stimulation Ontology label: Spinal Cord Stimulation NCIT:C21023

Transcutaneous spinal cord stimulation paired with gait training has early pediatric case-series evidence for feasibility and walking-function improvement after AFM-related incomplete spinal cord injury. This is an investigational rehabilitation adjunct rather than established standard care.

Target Phenotypes: Limb muscle weakness HP:0003690

Show evidence (1 reference)

DOI:10.3390/children11091116 SUPPORT Human Clinical

"safe and clinically feasible intervention"

A four-child case series supports feasibility and possible walking benefit but remains preliminary evidence.

Reconstructive surgery for persistent paralysis

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Selected patients with persistent severe upper-extremity paralysis after AFM may undergo reconstructive procedures such as nerve transfer, muscle-tendon transfer, or free muscle transfer. Evidence remains observational and procedure selection depends on residual donor-nerve and synergistic-muscle function.

Target Phenotypes: Upper limb muscle weakness HP:0003484

Show evidence (1 reference)

DOI:10.2106/JBJS.OA.23.00143 SUPPORT Human Clinical

"nerve transfer, muscle-tendon transfer, or free muscle transfer"

This retrospective cohort supports reconstructive surgery as a selected intervention for persistent AFM upper-extremity paralysis.

Immunomodulatory acute therapies

Action: Pharmacotherapy NCIT:C15986

Intravenous immunoglobulin, corticosteroids, and plasma exchange have been used empirically in AFM, especially early in the syndrome when mimics remain possible. Available clinical evidence does not establish that these therapies reverse AFM motor neuron injury, so this entry models them as empiric and uncertain rather than proven disease-modifying treatment. Preclinical EV-D68 AFM-model data further caution against assuming benefit from corticosteroids.

Show evidence (2 references)

PMID:26621554 SUPPORT Human Clinical

"intravenous immunoglobulin, corticosteroids, or plasma exchange"

The case series documents real-world use of immune therapies but also persistent deficits, so it supports exposure rather than proven efficacy.

PMID:28968718 SUPPORT Model Organism

"Dexamethasone treatment worsened motor impairment, increased mortality, and increased viral loads."

Mouse-model evidence specifically cautions that corticosteroid exposure may worsen EV-D68 paralytic myelitis biology, although it is not direct human treatment evidence.

🌍

Environmental Factors

EV-D68 respiratory circulation and wastewater seasonality

EV-D68 circulation is the main environmental infectious exposure context for AFM surveillance. Wastewater monitoring can detect EV-D68 seasonality and regional timing before or alongside clinical respiratory diagnoses, which may help public-health preparedness even though AFM remains rare relative to EV-D68 infection.

Show evidence (2 references)

PMID:41853773 SUPPORT Other

"Enterovirus D68 (EV-D68) can cause severe respiratory illness and acute flaccid myelitis (AFM)"

The wastewater surveillance study frames EV-D68 as a respiratory pathogen relevant to AFM preparedness.

PMID:41853773 SUPPORT Other

"We observed a biennial EV-D68 pattern with a national peak in September 2024"

Wastewater data support the seasonal and biennial environmental circulation pattern encoded here.

🔬

Diagnosis

MRI-centered AFM evaluation

Suspected AFM evaluation centers on urgent neurologic examination and MRI of the entire spinal cord and brainstem to detect gray-matter lesions. CSF analysis, respiratory and stool testing, poliovirus exclusion, and early electrodiagnostic testing help characterize inflammation, seek an infectious association, and distinguish peripheral neuropathy.

magnetic resonance imaging procedure NCIT:C16809

Results: Longitudinal spinal cord gray-matter lesions, especially anterior horn involvement, support AFM in the right clinical context.

Show evidence (2 references)

PMID:26621554 SUPPORT Human Clinical

"spinal gray matter lesions"

Pediatric case series supports MRI detection of spinal gray matter lesions as a key recognition feature.

PMID:33357469 SUPPORT Human Clinical

"clinical, neuroimaging, and cerebrospinal fluid characteristics"

The Lancet review supports an integrated diagnostic workup rather than a single confirmatory test.

CSF and respiratory or stool enterovirus testing

CSF cell count and protein are supportive, while respiratory and stool specimens should be collected early for enterovirus typing and poliovirus exclusion. A negative CSF PCR does not exclude AFM or an enterovirus association because viral RNA is rarely recovered from CSF.

Results: Pleocytosis supports CNS inflammation; enterovirus detection outside CSF can support an association but does not independently prove viral causation of the neurologic syndrome.

Show evidence (2 references)

PMID:31409689 SUPPORT Human Clinical

"An infectious agent is only rarely detected in cerebrospinal fluid (CSF)."

Rare CSF detection explains why negative CSF PCR cannot exclude AFM.

PMID:26720027 SUPPORT Human Clinical

"No pathogens were isolated from the cerebrospinal fluid."

The 59-case series illustrates the low yield of CSF pathogen testing.

Mimic exclusion

AFM diagnosis requires careful exclusion of other causes of acute flaccid paralysis, especially Guillain-Barre syndrome, spinal cord stroke, acute transverse myelitis, poliomyelitis, and compressive or structural spinal cord disease.

Key mimics include Guillain-Barre syndrome, spinal cord infarction, transverse myelitis, poliomyelitis, and structural spinal cord disease.

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis"

The clinical review explicitly lists these major AFM mimics.

🩻

Imaging Findings

Longitudinal spinal gray-matter T2 hyperintensity on MRI VERY_FREQUENT

T2 hyperintensity centered in spinal gray matter, often longitudinally extensive and most conspicuous in the anterior horns, is the defining radiologic AFM finding. A predominantly gray-matter lesion spanning at least one spinal segment is part of the confirmed surveillance case definition.

Mri Diagnostic Extensive

spinal cord lesion HP:0100561 ventral horn of spinal cord UBERON:0002257 spinal cord gray matter lesion HP:0100561

Show evidence (2 references)

PMID:31409689 SUPPORT Human Clinical

"magnetic resonance imaging evidence of a predominantly gray matter lesion that spans at least one spinal segment"

The published surveillance definition establishes the diagnostic morphology.

PMID:26720027 SUPPORT Human Clinical

"Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging"

Fifty-six of 59 cases support the very-frequent frequency band.

📈

Progression

Rapid progression to acute nadir

Weakness progresses over hours to days. In a direct pediatric comparison, AFM reached nadir sooner than GBS, reinforcing the need for prompt MRI, respiratory monitoring, and specimen collection.

Show evidence (1 reference)

PMID:34747551 SUPPORT Human Clinical

"shorter interval between onset of weakness and nadir (3 vs. 8 days, p < 0.001)"

The comparative cohort places median AFM nadir at three days.

Chronic motor deficit with partial functional recovery

Persistent focal paralysis is common, although disability and activity of daily living can continue to improve over years. Motor recovery is generally less complete than recovery of nonmotor neurologic findings.

Show evidence (2 references)

PMID:33388543 SUPPORT Human Clinical

"AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis."

Three-year follow-up establishes persistence of focal motor deficits.

PMID:33388543 SUPPORT Human Clinical

"Disability level of patients with AFM, however, generally improved at the three-year time point."

Functional improvement despite residual paralysis gives a more nuanced prognosis than either full recovery or fixed disability.

Long-term respiratory morbidity after acute respiratory failure

Children requiring respiratory support during the acute illness have a higher risk of chronic respiratory support, health-care use, and prolonged neurologic disability.

Show evidence (1 reference)

PMID:39657203 SUPPORT Human Clinical

"Among children with respiratory failure, 6 patients (75%) required follow-up respiratory support."

Six of eight children with acute respiratory failure required later respiratory support, defining a high-risk prognostic subgroup.

🌍

Epidemiology

Rare pediatric disease with biennial outbreaks

AFM is rare, occurs mainly in children, and has shown seasonal biennial outbreak peaks in the United States and other regions since 2012.

Show evidence (2 references)

PMID:33357469 SUPPORT Human Clinical

"mainly affecting children"

The Lancet review summarizes AFM as a mainly pediatric polio-like illness.

PMID:32143233 SUPPORT Human Clinical

"every 2 years since 2012"

This clinical review describes the US biennial seasonal peak pattern.

United States surveillance since the 2018 peak

CDC surveillance found only 28-47 confirmed US AFM cases per year during 2019-2022. Counts remained low despite increased EV-D68 circulation in 2022, showing that respiratory-virus circulation alone does not reliably predict AFM burden and that additional host, viral, or exposure factors are likely.

Show evidence (2 references)

PMID:38300829 SUPPORT Human Clinical

"The number of AFM cases was low during 2019-2022 (28-47 cases per year)"

The CDC surveillance report supplies the post-2018 annual range.

PMID:38300829 SUPPORT Human Clinical

"the number of cases remained low in 2022 despite evidence of increased EV-D68 circulation in the United States"

The discordance between respiratory circulation and paralysis motivates explicit uncertainty about the determinants of neuroinvasive disease.

Netherlands pediatric incidence

Retrospective multicenter surveillance in the Netherlands found a very low mean pediatric AFM incidence during 2014-2019.

0.06–? cases per 100000 children per year

Show evidence (1 reference)

PMID:36268734 SUPPORT Human Clinical

"0.06/100,000 children/year"

The Dutch cohort reports the pediatric mean incidence estimate encoded here.

Orphanet onset spectrum

Orphanet records AFM onset across infancy, childhood, adolescence, and adulthood, consistent with a predominantly pediatric disorder that can also occur outside childhood.

Show evidence (2 references)

ORPHA:623801 SUPPORT Other

"Age of onset: Childhood"

Orphanet records childhood onset among AFM natural-history categories.

ORPHA:623801 SUPPORT Other

"Age of onset: Adult"

Orphanet also records adult onset, supporting a broad age range despite pediatric predominance.

Population-based pediatric risk factors

A closed-population pediatric cohort identified male sex, Asian ancestry, asthma or atopic dermatitis history, and head injury history as AFM risk factors. These associations support host-susceptibility modeling but do not establish a Mendelian or deterministic risk mechanism.

Show evidence (1 reference)

PMID:30985511 SUPPORT Human Clinical

"Risk factors included male sex, Asian ancestry and history of asthma, atopic dermatitis or head injury."

The California population-based cohort provides the specific risk-factor associations summarized here.

European EV-D68-associated AFM surveillance

A European ENPEN survey found 130 reported AFM cases across 14 countries during 2016-2023, including 48 EV-D68-laboratory-confirmed cases; most occurred in years of increased EV-D68 circulation. The same report cautions that structural AFM surveillance was limited, so counts should be interpreted as incomplete surveillance data.

Show evidence (2 references)

PMID:40444374 SUPPORT Human Clinical

"The survey revealed 130 AFM cases for 14 countries, with 48 (37%) EV-D68-laboratory-confirmed."

The European survey directly supports the cross-country case count and EV-D68-confirmed subset.

PMID:40444374 SUPPORT Human Clinical

"70% (n = 91) occurred in 2016, 2018 and 2022, when EV-D68 circulation increased."

This supports the temporal association between AFM occurrence and increased EV-D68 circulation in Europe.

🦠

Infectious Agent

Enterovirus D68

EV-D68 is the best-supported infectious exposure associated with epidemic AFM. Temporal clustering, respiratory detections, CSF enterovirus-antibody enrichment, animal causation, and human neural-model infection support a causal role, but viral RNA is rarely found in CSF and not every AFM case is attributable to EV-D68.

Enterovirus D68 NCBITaxon:42789

Show evidence (3 references)

PMID:31409689 SUPPORT Human Clinical

"antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%)"

CSF enterovirus-antibody enrichment supplies biologic evidence of prior enterovirus exposure when viral nucleic acid is no longer detectable.

PMID:31409689 SUPPORT Human Clinical

"EV RNA was confirmed in CSF from only 1 adult AFM case"

Rare direct CSF detection is important negative context: it limits patient-level etiologic confirmation despite the broader association.

PMID:42066114 SUPPORT Human Clinical

"AFM case-control studies did not (OR 0.86, 95% CI 0.40-1.86, k = 20)"

The 2026 meta-analysis finds design-dependent and heterogeneous estimates, preventing a simplistic claim that EV-D68 explains every AFM case.

Enterovirus A71

EV-A71 is a recognized non-polio enterovirus associated with some AFM cases, but it is not the principal explanation for the recent North American biennial AFM pattern. Viral association is represented here as an agent relationship rather than as a formal disease subtype.

Enterovirus A71 NCBITaxon:39054

Show evidence (1 reference)

PMID:36268734 SUPPORT Human Clinical

"EV-D68 and EV-A71"

The surveillance report identifies both viruses among non-polio enteroviruses associated with AFM.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Acute Flaccid Myelitis:

Guillain-Barre syndrome MONDO:0016218

Overlapping Features GBS also causes acute weakness and areflexia, but weakness is usually more symmetric, sensory deficits are more common, progression to nadir is slower, CSF protein is higher relative to leukocytes, and spinal gray-matter lesions favor AFM.

Distinguishing Features

AFM reached nadir sooner in a pediatric comparison (3 versus 8 days).
Asymmetric weakness and lack of sensory deficits favored AFM.
Spinal-cord lesions were found only in AFM in the comparative cohort.

Show evidence (1 reference)

PMID:34747551 SUPPORT Human Clinical

"shorter interval between onset of weakness and nadir (3 vs. 8 days, p < 0.001), more often had asymmetric limb weakness (58% vs. 0%, p < 0.001), and less frequently had sensory deficits (0% vs. 40%, p < 0.001)"

The direct pediatric comparison supplies the principal early distinctions.

Acute transverse myelitis Not Yet Curated MONDO:0015342

Overlapping Features Transverse myelitis can produce acute weakness and a spinal lesion, but a sensory level, bowel or bladder dysfunction, upper-motor-neuron evolution, and a lesion not selectively centered in anterior-horn gray matter favor transverse myelitis over AFM.

Distinguishing Features

Sensory and autonomic spinal-cord dysfunction are more prominent.
MRI involvement is not restricted to the anterior-horn gray-matter pattern.

Show evidence (1 reference)

PMID:36996587 SUPPORT Human Clinical

"Patients initially classified as probable or possible AFM were most commonly diagnosed with transverse myelitis (16/25)."

This diagnostic study establishes transverse myelitis as the main probable/possible AFM mimic.

Poliomyelitis Not Yet Curated MONDO:0017373

Overlapping Features Poliomyelitis can be clinically and anatomically indistinguishable from AFM. Travel and vaccination history plus urgent stool testing for poliovirus are required because a non-polio AFM label must not delay public-health response to possible poliovirus.

Distinguishing Features

Poliovirus detection establishes poliomyelitis rather than non-polio AFM.
Epidemiologic exposure and immunization history change the pretest probability.

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"striking similarities to cases of poliomyelitis"

The clinical review supports the close phenotypic overlap.

Spinal cord infarction

Overlapping Features Spinal cord infarction can cause abrupt flaccid weakness and initially mimic AFM. Hyperacute maximal deficit, a vascular or hypotensive context, restricted diffusion, and a vascular-territory pattern favor infarction.

Distinguishing Features

Deficit is often maximal at onset rather than progressing over several days.
Diffusion restriction and vascular-territory MRI findings favor infarction.

Show evidence (1 reference)

PMID:32143233 SUPPORT Human Clinical

"Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis."

The AFM clinical review explicitly includes spinal cord stroke among major mimics.

📊

Related Datasets

Single-cell RNA sequencing of EV-D68-infected human spinal cord organoids DOI:10.3389/fmicb.2025.1698639

Single-cell transcriptomic comparison of naive human spinal-cord organoids and organoids infected with two contemporary EV-D68 strains, resolving neuronal and glial composition, viral tropism, and host transcriptional responses.

human SINGLE CELL RNA SEQ

Conditions: Naive human spinal cord organoids US/IL/14-18952 EV-D68 infection US/MA/18-23089 EV-D68 infection

Findings

The two tested EV-D68 strains showed distinct cell tropism and host responses.

"Upon infection with 2 EV-D68 strains, US/IL/14-18952 (a B2 strain) and US/MA/18-23089 (a B3 strain), we observed distinct viral tropism and host transcriptional responses."

Show evidence (1 reference)

DOI:10.3389/fmicb.2025.1698639 SUPPORT In Vitro

"we observed distinct viral tropism and host transcriptional responses"

The source directly states the dataset-level finding.

DOI:10.3389/fmicb.2025.1698639

Show evidence (1 reference)

DOI:10.3389/fmicb.2025.1698639 SUPPORT In Vitro

"we profiled naive and EV-D68-infected human spinal cord organoids (hSCOs) derived from induced pluripotent stem cells (iPSCs) using single-cell RNA sequencing (scRNA-seq)"

The publication directly describes the dataset design and assay.

🔬

Clinical Trials

NCT02144935 NOT_APPLICABLE COMPLETED

CAPTURE was an observational pediatric registry and data repository for transverse myelitis or AFM, using surveys, interviews, and medical-record review to characterize recovery and inform future clinical trials.

Show evidence (1 reference)

clinicaltrials:NCT02144935 SUPPORT Human Clinical

"transverse myelitis (TM) or acute flaccid myelitis (AFM)"

ClinicalTrials.gov confirms that CAPTURE enrolled pediatric TM or AFM patients for registry-based outcomes follow-up.

NCT03499366 NOT_APPLICABLE UNKNOWN

European observational follow-up study of pediatric acute flaccid myelitis associated with EV-D68 infection, designed to assess clinical outcome and correlations with severity, treatment, and MRI findings.

Show evidence (1 reference)

clinicaltrials:NCT03499366 SUPPORT Human Clinical

"acute flaccid paresis associated with enterovirus D68 infection"

ClinicalTrials.gov identifies an EV-D68-associated pediatric AFM follow-up study.

🧫

Experimental Models

Human iPSC-derived spinal cord organoids infected with EV-D68 ORGANOID

Two three-dimensional human spinal-cord organoid systems, one enriched for spinal motor neurons and one containing multiple neuronal and glial lineages, model productive infection by contemporary EV-D68 strains. They reproduce neural tropism but not the immune-cell environment or the full route from respiratory infection to human paralysis.

Organism

human NCBITaxon:9606

Tissue

spinal cord UBERON:0002240

Cell source

Human induced pluripotent stem cell-derived spinal neural cells

Culture

Three-dimensional multicellular spinal cord organoids

Publication

DOI:10.1128/mbio.01058-23

Pathograph links

Spinal Neural Cell Tropism and Infection Tests whether historical and contemporary EV-D68 strains productively infect human spinal neural populations.

Show evidence (1 reference)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"productively infected with contemporary strains, but not a historic strain, of EV-D68"

The organoid infection directly models the curated tropism mechanism.

Spinal Gray Matter Inflammation and Motor Neuron Injury Separates productive viral infection from overt cytopathic injury and motivates testing secondary immune-mediated damage.

Show evidence (1 reference)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"secondary injury from the immune response likely contributes to pathogenesis"

The model motivates, but does not itself reproduce, secondary immune injury.

Findings

Contemporary, but not historical, EV-D68 strains productively infect spinal cord organoids.

"These hSCOs can be productively infected with contemporary strains, but not a historic strain, of EV-D68 and produce extracellular virus for at least 2 weeks without appreciable cytopathic effect."

Show evidence (1 reference)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"produce extracellular virus for at least 2 weeks without appreciable cytopathic effect"

This exact observation supports the finding.

Cell tropism differs between contemporary EV-D68 strains.

"US/IL/14-18952 showed a significant preference for neurons, while US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes and OPCs."

Show evidence (1 reference)

DOI:10.3389/fmicb.2025.1698639 SUPPORT In Vitro

"US/IL/14-18952 showed a significant preference for neurons"

The single-cell study directly supports strain-specific tropism.

Show evidence (2 references)

DOI:10.1128/mbio.01058-23 SUPPORT In Vitro

"produce extracellular virus for at least 2 weeks without appreciable cytopathic effect"

This establishes sustained productive infection while showing that viral cytopathy alone does not reproduce the human injury phenotype.

DOI:10.3389/fmicb.2025.1698639 SUPPORT In Vitro

"US/IL/14-18952 showed a significant preference for neurons, while US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes and OPCs."

Single-cell profiling distinguishes strain-specific target-cell preferences.

🐁

Animal Models

mouse Viral infection mouse model

Neonatal mouse models infected with contemporary EV-D68 outbreak strains develop paralytic myelitis resembling human AFM, with virus and viral genome in spinal cord and motor neuron loss in anterior horns corresponding to paralyzed limbs.

Species

mouse

Background

neonatal mice experimentally infected with EV-D68

Show evidence (2 references)

PMID:28231269 SUPPORT Model Organism

"four EV-D68 strains from the 2014 outbreak (out of five tested) produced a paralytic disease in mice resembling human AFM."

This animal-model study supports EV-D68 as capable of producing an AFM-like paralytic phenotype in neonatal mice.

PMID:28231269 SUPPORT Model Organism

"infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs."

The model recapitulates the anterior-horn motor neuron injury central to human AFM pathophysiology.

{ }

Source YAML

click to show

name: Acute Flaccid Myelitis
creation_date: "2026-05-16T17:34:01Z"
category: Neurological Disorder
disease_term:
  preferred_term: acute flaccid myelitis
  term:
    id: MONDO:0100115
    label: acute flaccid myelitis
parents:
- Myelitis
- Acute disease
- Central nervous system disorder
description: >-
  Acute flaccid myelitis (AFM) is a rare, acute, polio-like neurologic
  syndrome, mainly reported in children, with rapid flaccid limb weakness and
  spinal cord gray-matter involvement. Most cases follow a febrile or
  respiratory prodrome. The clinical syndrome localizes predominantly to lower
  motor neurons in the anterior horn of the spinal cord, can involve cranial,
  bulbar, axial, and respiratory muscles, and is strongly associated
  epidemiologically with non-polio enteroviruses, especially enterovirus D68.
external_assertions:
- name: Orphanet acute flaccid myelitis record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:623801
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=623801
  description: >-
    Orphanet's ORPHA:623801 structured record for acute flaccid myelitis
    provides the rare-disease identifier, exact MONDO cross-reference, narrower
    ICD-10 mapping, MeSH and UMLS cross-references, broad onset categories, and
    international incidence annotations used to cross-check this entry.
  evidence:
  - reference: ORPHA:623801
    reference_title: Acute flaccid myelitis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0100115 | Exact"
    explanation: >-
      Orphanet maps ORPHA:623801 exactly to the MONDO disease identifier used by
      this entry.
  - reference: ORPHA:623801
    reference_title: Acute flaccid myelitis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:G04.8 | Narrower"
    explanation: >-
      The Orphanet cross-reference table records a narrower ICD-10 mapping for
      AFM.
definitions:
- name: Clinical and radiologic AFM syndrome
  definition_type: CASE_DEFINITION
  description: >-
    AFM is defined clinically by acute flaccid limb weakness with objective
    evidence of spinal cord gray-matter involvement, typically by MRI, and/or
    supporting cerebrospinal-fluid inflammation after exclusion of mimics such
    as Guillain-Barre syndrome, spinal cord infarction, poliomyelitis, and
    transverse myelitis.
  criteria_sets:
  - name: Core AFM features
    core_clinical_characteristics:
    - preferred_term: acute flaccid limb weakness
      term:
        id: HP:0003690
        label: Limb muscle weakness
      description: Rapid onset limb weakness with lower motor neuron features.
    - preferred_term: spinal cord gray matter lesion
      term:
        id: HP:0100561
        label: Spinal cord lesion
      description: >-
        MRI lesion centered in spinal cord gray matter, especially the anterior
        horns.
    - preferred_term: CSF pleocytosis
      term:
        id: HP:0012229
        label: CSF pleocytosis
      description: >-
        Supportive inflammatory cerebrospinal-fluid finding in probable or
        definite AFM criteria.
    evidence:
    - reference: PMID:31409689
      reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classification criteria for a confirmed AFM case are acute flaccid limb
        weakness and magnetic resonance imaging evidence of a predominantly gray
        matter lesion that spans at least one spinal segment
      explanation: >-
        This reproduces the surveillance definition for confirmed AFM and
        directly supports the two required core criteria.
  evidence:
  - reference: PMID:27422805
    reference_title: "Acute flaccid myelitis: A clinical review of US cases 2012-2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute flaccid limb weakness with spinal cord gray matter lesions"
    explanation: >-
      The US case review directly supports the core clinical-radiologic
      definition used here.
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no single sensitive and specific test for AFM"
    explanation: >-
      The Lancet review supports modeling AFM as a syndromic diagnosis requiring
      integrated clinical, MRI, CSF, and exclusionary evidence.
infectious_agent:
- name: Enterovirus D68
  infectious_agent_term:
    preferred_term: Enterovirus D68
    term:
      id: NCBITaxon:42789
      label: Enterovirus D68
  description: >-
    EV-D68 is the best-supported infectious exposure associated with epidemic
    AFM. Temporal clustering, respiratory detections, CSF enterovirus-antibody
    enrichment, animal causation, and human neural-model infection support a
    causal role, but viral RNA is rarely found in CSF and not every AFM case is
    attributable to EV-D68.
  evidence:
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%)"
    explanation: >-
      CSF enterovirus-antibody enrichment supplies biologic evidence of prior
      enterovirus exposure when viral nucleic acid is no longer detectable.
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EV RNA was confirmed in CSF from only 1 adult AFM case"
    explanation: >-
      Rare direct CSF detection is important negative context: it limits
      patient-level etiologic confirmation despite the broader association.
  - reference: PMID:42066114
    reference_title: "Enterovirus D68 and Acute Neurologic Outcomes: A Systematic Review and Meta-Analysis (2010-2025)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AFM case-control studies did not (OR 0.86, 95% CI 0.40-1.86, k = 20)"
    explanation: >-
      The 2026 meta-analysis finds design-dependent and heterogeneous estimates,
      preventing a simplistic claim that EV-D68 explains every AFM case.
- name: Enterovirus A71
  infectious_agent_term:
    preferred_term: Enterovirus A71
    term:
      id: NCBITaxon:39054
      label: Enterovirus A71
  description: >-
    EV-A71 is a recognized non-polio enterovirus associated with some AFM cases,
    but it is not the principal explanation for the recent North American
    biennial AFM pattern. Viral association is represented here as an agent
    relationship rather than as a formal disease subtype.
  evidence:
  - reference: PMID:36268734
    reference_title: "Epidemiology of acute flaccid myelitis in children in the Netherlands, 2014 to 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EV-D68 and EV-A71"
    explanation: >-
      The surveillance report identifies both viruses among non-polio
      enteroviruses associated with AFM.
mechanistic_hypotheses:
- hypothesis_group_id: ev_d68_direct_neuroinvasion_model
  hypothesis_label: EV-D68 Direct Neuroinvasion Model
  status: CANONICAL
  description: >-
    In the best-supported model for epidemic AFM, EV-D68 respiratory infection
    is followed rarely by CNS access, receptor-mediated infection of spinal
    neural cells, and anterior-horn motor-neuron injury. Epidemiologic and human
    CSF evidence support the association, while mouse and organoid systems show
    that contemporary EV-D68 strains can infect neural tissue and cause
    paralytic myelitis. The model does not imply virologic confirmation in every
    patient.
  evidence:
  - reference: PMID:28231269
    reference_title: A mouse model of paralytic myelitis caused by enterovirus D68.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Virus isolated from spinal cords of infected mice transmitted disease when injected into naïve mice, fulfilling Koch's postulates in this model."
    explanation: >-
      Experimental transmission establishes direct causation in the mouse model,
      while the qualification "in this model" prevents overextension to humans.
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the disease appears to be caused by non-polio enterovirus infection"
    explanation: >-
      The clinical review identifies non-polio enterovirus infection as the
      leading human etiologic model.
- hypothesis_group_id: secondary_immune_mediated_injury_model
  hypothesis_label: Secondary Immune-Mediated Neural Injury Model
  status: EMERGING
  description: >-
    Direct neural infection may initiate AFM without being sufficient to cause
    the full motor-neuron injury. Persistent productive infection with little
    cytopathic effect in human spinal-cord organoids suggests that host immune
    responses or other secondary injury mechanisms may contribute to neuronal
    loss.
  evidence:
  - reference: DOI:10.1128/mbio.01058-23
    reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      EV-D68 infection is not the sole mediator of neuronal cell death in the
      spinal cord in those with AFM and that secondary injury from the immune
      response likely contributes to pathogenesis.
    explanation: >-
      The human organoid study explicitly proposes secondary immune injury after
      observing prolonged productive infection without appreciable cytopathy.
epidemiology:
- name: Rare pediatric disease with biennial outbreaks
  description: >-
    AFM is rare, occurs mainly in children, and has shown seasonal biennial
    outbreak peaks in the United States and other regions since 2012.
  evidence:
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainly affecting children"
    explanation: >-
      The Lancet review summarizes AFM as a mainly pediatric polio-like illness.
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "every 2 years since 2012"
    explanation: >-
      This clinical review describes the US biennial seasonal peak pattern.
- name: United States surveillance since the 2018 peak
  description: >-
    CDC surveillance found only 28-47 confirmed US AFM cases per year during
    2019-2022. Counts remained low despite increased EV-D68 circulation in 2022,
    showing that respiratory-virus circulation alone does not reliably predict
    AFM burden and that additional host, viral, or exposure factors are likely.
  evidence:
  - reference: PMID:38300829
    reference_title: "Surveillance for Acute Flaccid Myelitis - United States, 2018-2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The number of AFM cases was low during 2019-2022 (28-47 cases per year)"
    explanation: >-
      The CDC surveillance report supplies the post-2018 annual range.
  - reference: PMID:38300829
    reference_title: "Surveillance for Acute Flaccid Myelitis - United States, 2018-2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the number of cases remained low in 2022 despite evidence of increased EV-D68 circulation in the United States"
    explanation: >-
      The discordance between respiratory circulation and paralysis motivates
      explicit uncertainty about the determinants of neuroinvasive disease.
- name: Netherlands pediatric incidence
  description: >-
    Retrospective multicenter surveillance in the Netherlands found a very low
    mean pediatric AFM incidence during 2014-2019.
  minimum_value: 0.06
  unit: cases per 100000 children per year
  evidence:
  - reference: PMID:36268734
    reference_title: "Epidemiology of acute flaccid myelitis in children in the Netherlands, 2014 to 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "0.06/100,000 children/year"
    explanation: >-
      The Dutch cohort reports the pediatric mean incidence estimate encoded
      here.
- name: Orphanet onset spectrum
  description: >-
    Orphanet records AFM onset across infancy, childhood, adolescence, and
    adulthood, consistent with a predominantly pediatric disorder that can also
    occur outside childhood.
  evidence:
  - reference: ORPHA:623801
    reference_title: Acute flaccid myelitis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: >-
      Orphanet records childhood onset among AFM natural-history categories.
  - reference: ORPHA:623801
    reference_title: Acute flaccid myelitis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: >-
      Orphanet also records adult onset, supporting a broad age range despite
      pediatric predominance.
- name: Population-based pediatric risk factors
  description: >-
    A closed-population pediatric cohort identified male sex, Asian ancestry,
    asthma or atopic dermatitis history, and head injury history as AFM risk
    factors. These associations support host-susceptibility modeling but do not
    establish a Mendelian or deterministic risk mechanism.
  evidence:
  - reference: PMID:30985511
    reference_title: "Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk factors included male sex, Asian ancestry and history of asthma, atopic dermatitis or head injury."
    explanation: >-
      The California population-based cohort provides the specific risk-factor
      associations summarized here.
- name: European EV-D68-associated AFM surveillance
  description: >-
    A European ENPEN survey found 130 reported AFM cases across 14 countries
    during 2016-2023, including 48 EV-D68-laboratory-confirmed cases; most
    occurred in years of increased EV-D68 circulation. The same report cautions
    that structural AFM surveillance was limited, so counts should be
    interpreted as incomplete surveillance data.
  evidence:
  - reference: PMID:40444374
    reference_title: "Acute flaccid myelitis in Europe between 2016 and 2023: indicating the need for better registration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The survey revealed 130 AFM cases for 14 countries, with 48 (37%) EV-D68-laboratory-confirmed."
    explanation: >-
      The European survey directly supports the cross-country case count and
      EV-D68-confirmed subset.
  - reference: PMID:40444374
    reference_title: "Acute flaccid myelitis in Europe between 2016 and 2023: indicating the need for better registration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "70% (n = 91) occurred in 2016, 2018 and 2022, when EV-D68 circulation increased."
    explanation: >-
      This supports the temporal association between AFM occurrence and
      increased EV-D68 circulation in Europe.
environmental:
- name: EV-D68 respiratory circulation and wastewater seasonality
  presence: PRESENT
  description: >-
    EV-D68 circulation is the main environmental infectious exposure context for
    AFM surveillance. Wastewater monitoring can detect EV-D68 seasonality and
    regional timing before or alongside clinical respiratory diagnoses, which
    may help public-health preparedness even though AFM remains rare relative to
    EV-D68 infection.
  effect: >-
    Increased EV-D68 circulation raises concern for AFM preparedness but is not
    sufficient on its own to predict individual paralysis risk.
  evidence:
  - reference: PMID:41853773
    reference_title: "Enterovirus D68 in United States wastewater: a longitudinal surveillance study integrating climatic, demographic, and clinical data."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Enterovirus D68 (EV-D68) can cause severe respiratory illness and acute flaccid myelitis (AFM)"
    explanation: >-
      The wastewater surveillance study frames EV-D68 as a respiratory pathogen
      relevant to AFM preparedness.
  - reference: PMID:41853773
    reference_title: "Enterovirus D68 in United States wastewater: a longitudinal surveillance study integrating climatic, demographic, and clinical data."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We observed a biennial EV-D68 pattern with a national peak in September 2024"
    explanation: >-
      Wastewater data support the seasonal and biennial environmental
      circulation pattern encoded here.
pathophysiology:
- name: Non-polio Enterovirus Respiratory Infection
  description: >-
    AFM most often occurs after a respiratory or febrile illness. EV-D68 is the
    leading epidemic-associated virus. Only a very small fraction of respiratory
    infections are followed by AFM, and the route and determinants that permit
    subsequent CNS access in children remain unresolved.
  locations:
  - preferred_term: respiratory system
    term:
      id: UBERON:0001004
      label: respiratory system
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  biological_processes:
  - preferred_term: response to virus
    modifier: INCREASED
    term:
      id: GO:0009615
      label: response to virus
  evidence:
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the disease appears to be caused by non-polio enterovirus infection"
    explanation: >-
      This clinical synthesis supports the enterovirus model while appropriately
      using probabilistic wording.
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cause of AFM remains elusive. An infectious agent is only rarely detected in cerebrospinal fluid (CSF)."
    explanation: >-
      Direct human etiologic confirmation is uncommon and the graph therefore
      does not represent neuroinvasion as proven in every case.
  downstream:
  - target: Prodromal respiratory tract infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - ev_d68_direct_neuroinvasion_model
    description: >-
      Respiratory enterovirus infection commonly produces the febrile or
      respiratory prodrome that precedes neurologic weakness.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In most cases, prodromal fever or respiratory symptoms occur"
      explanation: The review links the prodrome temporally to AFM onset.
  - target: MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ev_d68_direct_neuroinvasion_model
    description: >-
      Respiratory infection precedes rare CNS access and neural-cell entry, but
      the route of spread and other intervening determinants are not established.
    evidence:
    - reference: PMID:40132641
      reference_title: MFSD6 is an entry receptor for enterovirus D68.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MFSD6 as a host entry factor for EV-D68"
      explanation: The receptor study establishes the downstream entry step.
- name: MFSD6- and ICAM5-Mediated EV-D68 Neural Cell Entry
  description: >-
    MFSD6 is a directly demonstrated EV-D68 entry receptor in respiratory and
    neural primary cells. ICAM5 is a proposed neuron-specific receptor and is
    retained as complementary, lower-tier evidence rather than treated as a
    universal AFM receptor mechanism.
  genes:
  - preferred_term: MFSD6
    term:
      id: hgnc:24711
      label: MFSD6
  - preferred_term: ICAM5
    term:
      id: hgnc:5348
      label: ICAM5
  biological_processes:
  - preferred_term: symbiont entry into host cell
    modifier: INCREASED
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  evidence:
  - reference: PMID:40132641
    reference_title: MFSD6 is an entry receptor for enterovirus D68.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knockout of MFSD6 expression abrogated EV-D68 infection in cell lines and primary cells corresponding to respiratory and neural cells."
    explanation: >-
      Genetic loss-of-function and primary-cell experiments directly support
      MFSD6-dependent entry.
  - reference: PMID:41467840
    reference_title: "Enterovirus D68 receptor usage: from static attachment to dynamic entry."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICAM-5) as a neuron-specific receptor that provides a molecular explanation for neurotropism in AFM."
    explanation: >-
      A receptor-usage review supports ICAM5 as a neuron-specific alternative,
      but this is weaker evidence than the MFSD6 perturbation experiments.
  downstream:
  - target: Spinal Neural Cell Tropism and Infection
    causal_link_type: DIRECT
    hypothesis_groups:
    - ev_d68_direct_neuroinvasion_model
    description: >-
      Receptor-dependent cell entry permits productive EV-D68 infection in
      susceptible neural cells.
    evidence:
    - reference: PMID:40132641
      reference_title: MFSD6 is an entry receptor for enterovirus D68.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MFSD6 localized to the plasma membrane and was required for viral entry into host cells."
      explanation: This directly links receptor availability to viral entry.
- name: Spinal Neural Cell Tropism and Infection
  description: >-
    Contemporary EV-D68 strains productively infect human spinal-cord organoids.
    Tropism differs by strain across neurons, cycling astrocytes, and
    oligodendrocyte precursor cells, indicating that neural susceptibility is
    neither uniform nor explained by motor neurons alone.
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: oligodendrocyte precursor cell
    term:
      id: CL:0002453
      label: oligodendrocyte precursor cell
  evidence:
  - reference: DOI:10.1128/mbio.01058-23
    reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "productively infected with contemporary strains, but not a historic strain, of EV-D68"
    explanation: >-
      Productive infection in human spinal-cord organoids establishes direct
      human-cell neural tropism and a strain effect.
  - reference: DOI:10.3389/fmicb.2025.1698639
    reference_title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "distinct viral tropism and host transcriptional responses"
    explanation: Single-cell profiling supports strain- and cell-type-specific tropism.
  downstream:
  - target: Spinal Gray Matter Inflammation and Motor Neuron Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - ev_d68_direct_neuroinvasion_model
    - secondary_immune_mediated_injury_model
    description: >-
      Neural infection can precede motor-neuron injury through direct viral
      effects and/or secondary inflammatory injury; their relative contribution
      in human AFM remains unresolved.
    evidence:
    - reference: DOI:10.1128/mbio.01058-23
      reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "secondary injury from the immune response likely contributes to pathogenesis"
      explanation: >-
        Organoid infection with limited cytopathy specifically supports an
        intervening secondary-injury mechanism.
    - reference: PMID:28231269
      reference_title: A mouse model of paralytic myelitis caused by enterovirus D68.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs."
      explanation: The mouse model links spinal infection to regional motor-neuron loss.
- name: Spinal Gray Matter Inflammation and Motor Neuron Injury
  description: >-
    AFM injury is centered on spinal gray matter and anterior-horn motor neurons.
    Cranial motor nuclei can also be involved, accounting for facial, bulbar,
    and respiratory manifestations that cannot be attributed to spinal anterior
    horns alone.
  locations:
  - preferred_term: ventral horn of spinal cord
    term:
      id: UBERON:0002257
      label: ventral horn of spinal cord
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  cell_types:
  - preferred_term: anterior horn motor neuron
    term:
      id: CL:2000048
      label: anterior horn motor neuron
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary site of injury in AFM is the anterior horn cells of the spinal cord"
    explanation: The clinical review identifies the principal anatomic lesion.
  downstream:
  - target: Spinal cord gray matter lesion
    causal_link_type: DIRECT
    description: >-
      Gray-matter injury is visualized as the characteristic spinal-cord MRI
      abnormality.
    evidence:
    - reference: PMID:26720027
      reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging"
      explanation: The clinical series directly links the lesion compartment to MRI signal.
  - target: CSF pleocytosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - secondary_immune_mediated_injury_model
    description: >-
      CNS inflammation can increase leukocytes in CSF, although pleocytosis is
      supportive rather than required or disease-specific.
    evidence:
    - reference: PMID:26720027
      reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "43 patients had cerebrospinal fluid pleocytosis"
      explanation: The case series quantifies the inflammatory CSF finding.
  - target: Segmental and Cranial Lower Motor Neuron Dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss or dysfunction of spinal and cranial motor neurons produces the
      characteristic lower-motor-neuron syndrome.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "resulting in a motor neuronopathy"
      explanation: The clinical review explicitly links anterior-horn injury to motor neuronopathy.
- name: Segmental and Cranial Lower Motor Neuron Dysfunction
  description: >-
    Dysfunction of segmental anterior-horn and cranial motor systems produces
    rapid flaccid weakness, depressed reflexes, asymmetry, and, when brainstem or
    respiratory motor pools are affected, facial, bulbar, or ventilatory
    impairment.
  locations:
  - preferred_term: ventral horn of spinal cord
    term:
      id: UBERON:0002257
      label: ventral horn of spinal cord
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."
    explanation: This defines the motor distribution beyond limb weakness.
  downstream:
  - target: Acute flaccid paralysis
    causal_link_type: DIRECT
    description: Motor-neuron dysfunction produces acute flaccid paralysis.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by acute flaccid paralysis"
      explanation: The review directly describes the resulting paralysis phenotype.
  - target: Acute limb weakness
    causal_link_type: DIRECT
    description: Segmental motor-neuron dysfunction produces abrupt limb weakness.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "acute-onset flaccid limb weakness"
      explanation: The review directly describes the core limb phenotype.
  - target: Asymmetric limb weakness
    causal_link_type: DIRECT
    description: Patchy segmental motor-pool injury often produces asymmetric weakness.
    evidence:
    - reference: PMID:34747551
      reference_title: "Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "asymmetric limb weakness (58% vs. 0%, p < 0.001)"
      explanation: The comparative cohort quantifies the asymmetric pattern.
  - target: Areflexia
    causal_link_type: DIRECT
    description: Lower-motor-neuron dysfunction interrupts the reflex arc.
    evidence:
    - reference: PMID:39163469
      reference_title: Acute Flaccid Myelitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "decreased or absent reflexes"
      explanation: The clinical summary describes the lower-motor-neuron reflex finding.
  - target: Cranial nerve palsy
    causal_link_type: DIRECT
    description: Cranial motor-system involvement can produce cranial neuropathies.
    evidence:
    - reference: PMID:31014167
      reference_title: "Acute Flaccid Myelitis Associated With Enterovirus D68: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "with cranial neuropathy"
      explanation: The review documents cranial neuropathy in AFM.
  - target: Facial weakness
    causal_link_type: DIRECT
    description: Facial motor involvement can cause weakness of facial musculature.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "bulbar, facial, and extraocular muscles may also be affected"
      explanation: The review directly includes facial motor involvement.
  - target: Bulbar palsy
    causal_link_type: DIRECT
    description: Brainstem motor involvement can impair bulbar function.
    evidence:
    - reference: PMID:32143233
      reference_title: "Acute Flaccid Myelitis: A Clinical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."
      explanation: The review directly includes bulbar involvement.
  - target: Respiratory insufficiency due to muscle weakness
    causal_link_type: DIRECT
    description: Respiratory motor-pool involvement can cause ventilatory failure.
    evidence:
    - reference: PMID:33357469
      reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "can invoke respiratory failure and other critical complications"
      explanation: The clinical review links profound motor weakness to respiratory failure.
phenotypes:
- name: Prodromal respiratory tract infection
  category: Respiratory
  description: >-
    Most AFM cases are preceded by a short febrile or upper respiratory illness,
    typically 1-10 days before the onset of weakness.
  phenotype_term:
    preferred_term: acute prodromal respiratory tract infection
    term:
      id: HP:0011947
      label: Respiratory tract infection
    temporality: ACUTE
  evidence:
  - reference: PMID:39163469
    reference_title: Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "upper respiratory tract infection"
    explanation: >-
      The clinical summary identifies a preceding upper respiratory infection;
      no frequency band is assigned because the available quantitative endpoint
      pooled respiratory and gastrointestinal prodromes.
- name: Acute flaccid paralysis
  category: Neurologic
  phenotype_term:
    preferred_term: acute flaccid paralysis
    term:
      id: HP:0003470
      label: Paralysis
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute flaccid paralysis"
    explanation: >-
      Acute flaccid paralysis is part of the core clinical description of AFM.
- name: Acute limb weakness
  category: Neurologic
  phenotype_term:
    preferred_term: acute limb weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute-onset flaccid limb weakness"
    explanation: >-
      The review identifies acute flaccid limb weakness as a defining feature.
- name: Asymmetric limb weakness
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Limb weakness is often asymmetric in AFM and helps distinguish AFM from
    Guillain-Barre syndrome in children with acute flaccid paralysis.
  phenotype_term:
    preferred_term: asymmetric limb weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: PMID:34747551
    reference_title: "Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "asymmetric limb weakness (58% vs. 0%, p < 0.001)"
    explanation: >-
      Fifty-eight percent of the AFM cohort had asymmetric weakness, supporting
      the frequent band and its value against GBS.
- name: Areflexia
  category: Neurologic
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:39163469
    reference_title: Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "decreased or absent reflexes"
    explanation: >-
      The StatPearls clinical summary supports decreased or absent reflexes as a
      classic AFM finding.
- name: Spinal cord gray matter lesion
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: spinal cord gray matter lesion
    term:
      id: HP:0100561
      label: Spinal cord lesion
  evidence:
  - reference: PMID:26720027
    reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging"
    explanation: >-
      Fifty-six of 59 cases had the MRI abnormality, supporting the
      very-frequent band.
- name: CSF pleocytosis
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: CSF pleocytosis
    term:
      id: HP:0012229
      label: CSF pleocytosis
  evidence:
  - reference: PMID:26720027
    reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "43 patients had cerebrospinal fluid pleocytosis"
    explanation: >-
      Forty-three of 59 cases had CSF pleocytosis, supporting the frequent band.
- name: Cranial nerve palsy
  category: Neurologic
  phenotype_term:
    preferred_term: Cranial nerve palsy
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: PMID:31014167
    reference_title: "Acute Flaccid Myelitis Associated With Enterovirus D68: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with cranial neuropathy"
    explanation: >-
      The EV-D68-associated AFM review describes cranial neuropathy among common
      presenting features.
- name: Facial weakness
  category: Neurologic
  phenotype_term:
    preferred_term: Facial weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."
    explanation: >-
      The review lists facial muscle involvement in the broader set of AFM
      muscle groups that can be affected.
- name: Bulbar palsy
  category: Neurologic
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected."
    explanation: >-
      The review lists bulbar involvement in the broader set of AFM muscle
      groups that can be affected.
- name: Respiratory insufficiency due to muscle weakness
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:39657203
    reference_title: "Pediatric Patients With Acute Flaccid Myelitis: Long-term Respiratory and Neurologic Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight patients (21.6%) had respiratory failure during the index hospitalization."
    explanation: >-
      Eight of 37 children had respiratory failure, directly supporting the
      occasional frequency band in this cohort.
imaging_findings:
- name: Longitudinal spinal gray-matter T2 hyperintensity on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: spinal cord lesion
    term:
      id: HP:0100561
      label: Spinal cord lesion
  description: >-
    T2 hyperintensity centered in spinal gray matter, often longitudinally
    extensive and most conspicuous in the anterior horns, is the defining
    radiologic AFM finding. A predominantly gray-matter lesion spanning at least
    one spinal segment is part of the confirmed surveillance case definition.
  located_in:
    preferred_term: ventral horn of spinal cord
    term:
      id: UBERON:0002257
      label: ventral horn of spinal cord
  spatial_extent: EXTENSIVE
  phenotype_term:
    preferred_term: spinal cord gray matter lesion
    term:
      id: HP:0100561
      label: Spinal cord lesion
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      magnetic resonance imaging evidence of a predominantly gray matter lesion
      that spans at least one spinal segment
    explanation: The published surveillance definition establishes the diagnostic morphology.
  - reference: PMID:26720027
    reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging"
    explanation: Fifty-six of 59 cases support the very-frequent frequency band.
diagnosis:
- name: MRI-centered AFM evaluation
  description: >-
    Suspected AFM evaluation centers on urgent neurologic examination and MRI of
    the entire spinal cord and brainstem to detect gray-matter lesions. CSF
    analysis, respiratory and stool testing, poliovirus exclusion, and early
    electrodiagnostic testing help characterize inflammation, seek an infectious
    association, and distinguish peripheral neuropathy.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: >-
    Longitudinal spinal cord gray-matter lesions, especially anterior horn
    involvement, support AFM in the right clinical context.
  evidence:
  - reference: PMID:26621554
    reference_title: Recognition and Management of Acute Flaccid Myelitis in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spinal gray matter lesions"
    explanation: >-
      Pediatric case series supports MRI detection of spinal gray matter lesions
      as a key recognition feature.
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical, neuroimaging, and cerebrospinal fluid characteristics"
    explanation: >-
      The Lancet review supports an integrated diagnostic workup rather than a
      single confirmatory test.
- name: CSF and respiratory or stool enterovirus testing
  description: >-
    CSF cell count and protein are supportive, while respiratory and stool
    specimens should be collected early for enterovirus typing and poliovirus
    exclusion. A negative CSF PCR does not exclude AFM or an enterovirus
    association because viral RNA is rarely recovered from CSF.
  results: >-
    Pleocytosis supports CNS inflammation; enterovirus detection outside CSF can
    support an association but does not independently prove viral causation of
    the neurologic syndrome.
  evidence:
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An infectious agent is only rarely detected in cerebrospinal fluid (CSF)."
    explanation: Rare CSF detection explains why negative CSF PCR cannot exclude AFM.
  - reference: PMID:26720027
    reference_title: "Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No pathogens were isolated from the cerebrospinal fluid."
    explanation: The 59-case series illustrates the low yield of CSF pathogen testing.
- name: Mimic exclusion
  description: >-
    AFM diagnosis requires careful exclusion of other causes of acute flaccid
    paralysis, especially Guillain-Barre syndrome, spinal cord stroke, acute
    transverse myelitis, poliomyelitis, and compressive or structural spinal
    cord disease.
  notes: >-
    Key mimics include Guillain-Barre syndrome, spinal cord infarction,
    transverse myelitis, poliomyelitis, and structural spinal cord disease.
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis"
    explanation: >-
      The clinical review explicitly lists these major AFM mimics.
differential_diagnoses:
- name: Guillain-Barre syndrome
  disease_term:
    preferred_term: Guillain-Barre syndrome
    term:
      id: MONDO:0016218
      label: Guillain-Barre syndrome
  description: >-
    GBS also causes acute weakness and areflexia, but weakness is usually more
    symmetric, sensory deficits are more common, progression to nadir is slower,
    CSF protein is higher relative to leukocytes, and spinal gray-matter lesions
    favor AFM.
  distinguishing_features:
  - AFM reached nadir sooner in a pediatric comparison (3 versus 8 days).
  - Asymmetric weakness and lack of sensory deficits favored AFM.
  - Spinal-cord lesions were found only in AFM in the comparative cohort.
  evidence:
  - reference: PMID:34747551
    reference_title: "Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      shorter interval between onset of weakness and nadir (3 vs. 8 days, p <
      0.001), more often had asymmetric limb weakness (58% vs. 0%, p < 0.001),
      and less frequently had sensory deficits (0% vs. 40%, p < 0.001)
    explanation: The direct pediatric comparison supplies the principal early distinctions.
- name: Acute transverse myelitis
  disease_term:
    preferred_term: acute transverse myelitis
    term:
      id: MONDO:0015342
      label: acute transverse myelitis
  description: >-
    Transverse myelitis can produce acute weakness and a spinal lesion, but a
    sensory level, bowel or bladder dysfunction, upper-motor-neuron evolution,
    and a lesion not selectively centered in anterior-horn gray matter favor
    transverse myelitis over AFM.
  distinguishing_features:
  - Sensory and autonomic spinal-cord dysfunction are more prominent.
  - MRI involvement is not restricted to the anterior-horn gray-matter pattern.
  evidence:
  - reference: PMID:36996587
    reference_title: "Pediatric acute flaccid myelitis: Evaluation of diagnostic criteria and differentiation from other causes of acute flaccid paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients initially classified as probable or possible AFM were most commonly diagnosed with transverse myelitis (16/25)."
    explanation: This diagnostic study establishes transverse myelitis as the main probable/possible AFM mimic.
- name: Poliomyelitis
  disease_term:
    preferred_term: poliomyelitis
    term:
      id: MONDO:0017373
      label: poliomyelitis
  description: >-
    Poliomyelitis can be clinically and anatomically indistinguishable from AFM.
    Travel and vaccination history plus urgent stool testing for poliovirus are
    required because a non-polio AFM label must not delay public-health response
    to possible poliovirus.
  distinguishing_features:
  - Poliovirus detection establishes poliomyelitis rather than non-polio AFM.
  - Epidemiologic exposure and immunization history change the pretest probability.
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "striking similarities to cases of poliomyelitis"
    explanation: The clinical review supports the close phenotypic overlap.
- name: Spinal cord infarction
  description: >-
    Spinal cord infarction can cause abrupt flaccid weakness and initially mimic
    AFM. Hyperacute maximal deficit, a vascular or hypotensive context, restricted
    diffusion, and a vascular-territory pattern favor infarction.
  distinguishing_features:
  - Deficit is often maximal at onset rather than progressing over several days.
  - Diffusion restriction and vascular-territory MRI findings favor infarction.
  evidence:
  - reference: PMID:32143233
    reference_title: "Acute Flaccid Myelitis: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis."
    explanation: The AFM clinical review explicitly includes spinal cord stroke among major mimics.
progression:
- phase: Rapid progression to acute nadir
  notes: >-
    Weakness progresses over hours to days. In a direct pediatric comparison,
    AFM reached nadir sooner than GBS, reinforcing the need for prompt MRI,
    respiratory monitoring, and specimen collection.
  evidence:
  - reference: PMID:34747551
    reference_title: "Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "shorter interval between onset of weakness and nadir (3 vs. 8 days, p < 0.001)"
    explanation: >-
      The comparative cohort places median AFM nadir at three days.
- phase: Chronic motor deficit with partial functional recovery
  notes: >-
    Persistent focal paralysis is common, although disability and activity of
    daily living can continue to improve over years. Motor recovery is generally
    less complete than recovery of nonmotor neurologic findings.
  evidence:
  - reference: PMID:33388543
    reference_title: Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis."
    explanation: >-
      Three-year follow-up establishes persistence of focal motor deficits.
  - reference: PMID:33388543
    reference_title: Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disability level of patients with AFM, however, generally improved at the three-year time point."
    explanation: >-
      Functional improvement despite residual paralysis gives a more nuanced
      prognosis than either full recovery or fixed disability.
- phase: Long-term respiratory morbidity after acute respiratory failure
  notes: >-
    Children requiring respiratory support during the acute illness have a
    higher risk of chronic respiratory support, health-care use, and prolonged
    neurologic disability.
  evidence:
  - reference: PMID:39657203
    reference_title: "Pediatric Patients With Acute Flaccid Myelitis: Long-term Respiratory and Neurologic Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among children with respiratory failure, 6 patients (75%) required follow-up respiratory support."
    explanation: >-
      Six of eight children with acute respiratory failure required later
      respiratory support, defining a high-risk prognostic subgroup.
treatments:
- name: Acute supportive care
  description: >-
    Acute management is primarily supportive and includes close monitoring for
    bulbar and respiratory muscle involvement, intensive-care support when
    needed, pain control, prevention of complications, and multidisciplinary
    neurologic and infectious-disease evaluation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "guide diagnosis, management, and rehabilitation"
    explanation: >-
      The Lancet review supports management and rehabilitation as central AFM
      care domains.
- name: Mechanical ventilatory support
  description: >-
    Respiratory muscle weakness or bulbar dysfunction can require intubation,
    invasive mechanical ventilation, or other airway and respiratory support.
  treatment_term:
    preferred_term: mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:39163469
    reference_title: Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "requires intubation and mechanical ventilation"
    explanation: >-
      The current clinical summary supports ventilatory support for severe AFM
      respiratory insufficiency.
- name: Physical therapy and rehabilitation
  description: >-
    Long-term care relies on early, intensive, and individualized
    rehabilitation, including physical therapy, occupational therapy, bracing,
    orthopedic monitoring, and functional support for residual motor deficits.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: PMID:33357469
    reference_title: "Acute flaccid myelitis: cause, diagnosis, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unique long-term rehabilitation needs"
    explanation: >-
      The Lancet review directly supports rehabilitation as a core AFM
      management need.
- name: Transcutaneous spinal cord stimulation with gait training
  description: >-
    Transcutaneous spinal cord stimulation paired with gait training has early
    pediatric case-series evidence for feasibility and walking-function
    improvement after AFM-related incomplete spinal cord injury. This is an
    investigational rehabilitation adjunct rather than established standard
    care.
  treatment_term:
    preferred_term: spinal cord stimulation
    term:
      id: NCIT:C21023
      label: Spinal Cord Stimulation
  target_phenotypes:
  - preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: DOI:10.3390/children11091116
    reference_title: Transcutaneous Spinal Cord Stimulation Enables Recovery of Walking in Children with Acute Flaccid Myelitis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "safe and clinically feasible intervention"
    explanation: >-
      A four-child case series supports feasibility and possible walking benefit
      but remains preliminary evidence.
- name: Reconstructive surgery for persistent paralysis
  description: >-
    Selected patients with persistent severe upper-extremity paralysis after AFM
    may undergo reconstructive procedures such as nerve transfer,
    muscle-tendon transfer, or free muscle transfer. Evidence remains
    observational and procedure selection depends on residual donor-nerve and
    synergistic-muscle function.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Upper limb muscle weakness
    term:
      id: HP:0003484
      label: Upper limb muscle weakness
  evidence:
  - reference: DOI:10.2106/JBJS.OA.23.00143
    reference_title: Midterm Outcomes of Surgical Reconstruction and Spontaneous Recovery of Upper-Extremity Paralysis Following Acute Flaccid Myelitis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nerve transfer, muscle-tendon transfer, or free muscle transfer"
    explanation: >-
      This retrospective cohort supports reconstructive surgery as a selected
      intervention for persistent AFM upper-extremity paralysis.
- name: Immunomodulatory acute therapies
  description: >-
    Intravenous immunoglobulin, corticosteroids, and plasma exchange have been
    used empirically in AFM, especially early in the syndrome when mimics remain
    possible. Available clinical evidence does not establish that these
    therapies reverse AFM motor neuron injury, so this entry models them as
    empiric and uncertain rather than proven disease-modifying treatment.
    Preclinical EV-D68 AFM-model data further caution against assuming benefit
    from corticosteroids.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:26621554
    reference_title: Recognition and Management of Acute Flaccid Myelitis in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intravenous immunoglobulin, corticosteroids, or plasma exchange"
    explanation: >-
      The case series documents real-world use of immune therapies but also
      persistent deficits, so it supports exposure rather than proven efficacy.
  - reference: PMID:28968718
    reference_title: Evaluating Treatment Efficacy in a Mouse Model of Enterovirus D68-Associated Paralytic Myelitis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dexamethasone treatment worsened motor impairment, increased mortality, and increased viral loads."
    explanation: >-
      Mouse-model evidence specifically cautions that corticosteroid exposure
      may worsen EV-D68 paralytic myelitis biology, although it is not direct
      human treatment evidence.
clinical_trials:
- name: NCT02144935
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    CAPTURE was an observational pediatric registry and data repository for
    transverse myelitis or AFM, using surveys, interviews, and medical-record
    review to characterize recovery and inform future clinical trials.
  evidence:
  - reference: clinicaltrials:NCT02144935
    reference_title: "Collaborative Assessment of Pediatric Transverse Myelitis: Understand, Reveal, Educate or CAPTURE Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transverse myelitis (TM) or acute flaccid myelitis (AFM)"
    explanation: >-
      ClinicalTrials.gov confirms that CAPTURE enrolled pediatric TM or AFM
      patients for registry-based outcomes follow-up.
- name: NCT03499366
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    European observational follow-up study of pediatric acute flaccid myelitis
    associated with EV-D68 infection, designed to assess clinical outcome and
    correlations with severity, treatment, and MRI findings.
  evidence:
  - reference: clinicaltrials:NCT03499366
    reference_title: A Clinical Observational Follow-up Study of European Pediatric Cases of Acute Flaccid Myelitis Associated With EV-D68 Infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute flaccid paresis associated with enterovirus D68 infection"
    explanation: >-
      ClinicalTrials.gov identifies an EV-D68-associated pediatric AFM follow-up
      study.
animal_models:
- species: mouse
  background: neonatal mice experimentally infected with EV-D68
  category: Viral infection mouse model
  description: >-
    Neonatal mouse models infected with contemporary EV-D68 outbreak strains
    develop paralytic myelitis resembling human AFM, with virus and viral genome
    in spinal cord and motor neuron loss in anterior horns corresponding to
    paralyzed limbs.
  associated_phenotypes:
  - Paralytic myelitis
  - Motor neuron loss
  - Limb paralysis
  evidence:
  - reference: PMID:28231269
    reference_title: A mouse model of paralytic myelitis caused by enterovirus D68.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "four EV-D68 strains from the 2014 outbreak (out of five tested) produced a paralytic disease in mice resembling human AFM."
    explanation: >-
      This animal-model study supports EV-D68 as capable of producing an
      AFM-like paralytic phenotype in neonatal mice.
  - reference: PMID:28231269
    reference_title: A mouse model of paralytic myelitis caused by enterovirus D68.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs."
    explanation: >-
      The model recapitulates the anterior-horn motor neuron injury central to
      human AFM pathophysiology.
experimental_models:
- name: Human iPSC-derived spinal cord organoids infected with EV-D68
  description: >-
    Two three-dimensional human spinal-cord organoid systems, one enriched for
    spinal motor neurons and one containing multiple neuronal and glial
    lineages, model productive infection by contemporary EV-D68 strains. They
    reproduce neural tropism but not the immune-cell environment or the full
    route from respiratory infection to human paralysis.
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: oligodendrocyte precursor cell
    term:
      id: CL:0002453
      label: oligodendrocyte precursor cell
  conditions:
  - Naive or EV-D68-infected human spinal cord organoids
  cell_source: Human induced pluripotent stem cell-derived spinal neural cells
  culture_system: Three-dimensional multicellular spinal cord organoids
  publication: DOI:10.1128/mbio.01058-23
  modeled_mechanisms:
  - target: Spinal Neural Cell Tropism and Infection
    description: >-
      Tests whether historical and contemporary EV-D68 strains productively
      infect human spinal neural populations.
    evidence:
    - reference: DOI:10.1128/mbio.01058-23
      reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "productively infected with contemporary strains, but not a historic strain, of EV-D68"
      explanation: The organoid infection directly models the curated tropism mechanism.
  - target: Spinal Gray Matter Inflammation and Motor Neuron Injury
    description: >-
      Separates productive viral infection from overt cytopathic injury and
      motivates testing secondary immune-mediated damage.
    evidence:
    - reference: DOI:10.1128/mbio.01058-23
      reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "secondary injury from the immune response likely contributes to pathogenesis"
      explanation: The model motivates, but does not itself reproduce, secondary immune injury.
  findings:
  - statement: Contemporary, but not historical, EV-D68 strains productively infect spinal cord organoids.
    supporting_text: >-
      These hSCOs can be productively infected with contemporary strains, but
      not a historic strain, of EV-D68 and produce extracellular virus for at
      least 2 weeks without appreciable cytopathic effect.
    evidence:
    - reference: DOI:10.1128/mbio.01058-23
      reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "produce extracellular virus for at least 2 weeks without appreciable cytopathic effect"
      explanation: This exact observation supports the finding.
  - statement: Cell tropism differs between contemporary EV-D68 strains.
    supporting_text: >-
      US/IL/14-18952 showed a significant preference for neurons, while
      US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes
      and OPCs.
    evidence:
    - reference: DOI:10.3389/fmicb.2025.1698639
      reference_title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "US/IL/14-18952 showed a significant preference for neurons"
      explanation: The single-cell study directly supports strain-specific tropism.
  evidence:
  - reference: DOI:10.1128/mbio.01058-23
    reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      produce extracellular virus for at least 2 weeks without appreciable
      cytopathic effect
    explanation: >-
      This establishes sustained productive infection while showing that viral
      cytopathy alone does not reproduce the human injury phenotype.
  - reference: DOI:10.3389/fmicb.2025.1698639
    reference_title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      US/IL/14-18952 showed a significant preference for neurons, while
      US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes
      and OPCs.
    explanation: Single-cell profiling distinguishes strain-specific target-cell preferences.
datasets:
- accession: DOI:10.3389/fmicb.2025.1698639
  title: Single-cell RNA sequencing of EV-D68-infected human spinal cord organoids
  description: >-
    Single-cell transcriptomic comparison of naive human spinal-cord organoids
    and organoids infected with two contemporary EV-D68 strains, resolving
    neuronal and glial composition, viral tropism, and host transcriptional
    responses.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  conditions:
  - Naive human spinal cord organoids
  - US/IL/14-18952 EV-D68 infection
  - US/MA/18-23089 EV-D68 infection
  publication: DOI:10.3389/fmicb.2025.1698639
  findings:
  - statement: The two tested EV-D68 strains showed distinct cell tropism and host responses.
    supporting_text: >-
      Upon infection with 2 EV-D68 strains, US/IL/14-18952 (a B2 strain) and
      US/MA/18-23089 (a B3 strain), we observed distinct viral tropism and host
      transcriptional responses.
    evidence:
    - reference: DOI:10.3389/fmicb.2025.1698639
      reference_title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we observed distinct viral tropism and host transcriptional responses"
      explanation: The source directly states the dataset-level finding.
  evidence:
  - reference: DOI:10.3389/fmicb.2025.1698639
    reference_title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we profiled naive and EV-D68-infected human spinal cord organoids (hSCOs) derived from induced pluripotent stem cells (iPSCs) using single-cell RNA sequencing (scRNA-seq)"
    explanation: The publication directly describes the dataset design and assay.
discussions:
- discussion_id: afm_ev_d68_human_causation_boundary
  prompt: >-
    What proportion of human AFM is directly caused by EV-D68 neuroinvasion,
    and which tests can establish that cause in an individual patient?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - infectious_agent#Enterovirus D68
  - pathophysiology#Non-polio Enterovirus Respiratory Infection
  rationale: >-
    Outbreak timing, respiratory detections, CSF antibodies, animal causation,
    and human-organoid infection form a coherent causal case. However, viral RNA
    is rarely detected in human CSF, case-control estimates are heterogeneous,
    and AFM is a syndrome with other infectious and noninfectious mimics. The
    graph therefore treats EV-D68 neuroinvasion as the canonical model for
    epidemic disease without assigning it to every case.
  evidence:
  - reference: PMID:42066114
    reference_title: "Enterovirus D68 and Acute Neurologic Outcomes: A Systematic Review and Meta-Analysis (2010-2025)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across 98 studies, the pooled odds ratio (OR) was 1.39 (95% CI 1.14-1.69),
      with high heterogeneity (I2 = 98.9%; prediction interval 0.24-8.15).
    explanation: The high heterogeneity quantifies uncertainty in human association estimates.
  - reference: PMID:31409689
    reference_title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supports the plausibility of a link between EV infection and AFM that warrants further investigation"
    explanation: The CSF-antibody study explicitly frames its evidence as plausibility, not proof.
  posed_date: "2026-07-20T00:00:00Z"
- discussion_id: afm_respiratory_wave_paralysis_mismatch
  prompt: >-
    Why do large EV-D68 respiratory waves not consistently produce parallel AFM
    peaks, and what host or viral determinants govern the rare paralytic outcome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - epidemiology#United States surveillance since the 2018 peak
  - environmental#EV-D68 respiratory circulation and wastewater seasonality
  rationale: >-
    AFM counts remained low during the 2022 US EV-D68 circulation increase.
    Prospective linked respiratory, wastewater, genomic, host-immunologic, and
    neurologic surveillance is needed to distinguish viral genotype, prior
    immunity, ascertainment, and host susceptibility effects.
  evidence:
  - reference: PMID:38300829
    reference_title: "Surveillance for Acute Flaccid Myelitis - United States, 2018-2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is unclear why EV-D68 circulation in 2022 was not associated with an increase in AFM cases"
    explanation: The national surveillance report states the mismatch directly.
  posed_date: "2026-07-20T00:00:00Z"
- discussion_id: afm_organoid_mouse_translation_limit
  prompt: >-
    Which immune and developmental features must be added to organoid and mouse
    systems to reproduce human AFM motor-neuron loss and recovery?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - experimental_models#Human iPSC-derived spinal cord organoids infected with EV-D68
  - animal_models#mouse
  rationale: >-
    Organoids show prolonged productive infection without appreciable cytopathy
    and lack a complete immune compartment. Mice are not native EV-D68 hosts and
    commonly require neonatal or modified conditions. These systems prove
    mechanistic capabilities but cannot determine the human balance between
    direct infection and immune-mediated injury.
  evidence:
  - reference: DOI:10.1128/mbio.01058-23
    reference_title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mice are not native hosts for EV-D68, and thus, existing mouse models use
      immunosuppressed or neonatal mice, mouse-adapted viruses, or intracranial
      inoculations.
    explanation: The organoid paper directly states key limitations of animal translation.
  posed_date: "2026-07-20T00:00:00Z"
review_notes: >-
  Comprehensive 2026 review corrected AFM identity and scope, replaced
  virus-associated pseudo-subtypes with infectious-agent relationships, and
  separated human association from experimental causation. The pathograph now
  connects infection, receptor-mediated entry, neural tropism, gray-matter and
  motor-neuron injury, lower-motor-neuron dysfunction, and every curated
  phenotype with typed, cited edges. MRI, CSF/virologic diagnosis, major
  differentials, long-term prognosis, supportive/rehabilitative/surgical care,
  experimental models, and surveillance uncertainty were audited.
references:
- reference: ORPHA:623801
  title: Acute flaccid myelitis
- reference: PMID:26621554
  title: Recognition and Management of Acute Flaccid Myelitis in Children.
- reference: PMID:27422805
  title: "Acute flaccid myelitis: A clinical review of US cases 2012-2015."
- reference: PMID:31014167
  title: "Acute Flaccid Myelitis Associated With Enterovirus D68: A Review."
- reference: PMID:31409689
  title: Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.
- reference: PMID:32143233
  title: "Acute Flaccid Myelitis: A Clinical Review."
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
- reference: PMID:33357469
  title: "Acute flaccid myelitis: cause, diagnosis, and management."
- reference: PMID:36268734
  title: "Epidemiology of acute flaccid myelitis in children in the Netherlands, 2014 to 2019."
- reference: PMID:39163469
  title: Acute Flaccid Myelitis.
- reference: PMID:40132641
  title: MFSD6 is an entry receptor for enterovirus D68.
- reference: clinicaltrials:NCT02144935
  title: "Collaborative Assessment of Pediatric Transverse Myelitis: Understand, Reveal, Educate or CAPTURE Study"
- reference: clinicaltrials:NCT03499366
  title: A Clinical Observational Follow-up Study of European Pediatric Cases of Acute Flaccid Myelitis Associated With EV-D68 Infection.
- reference: DOI:10.15585/mmwr.mm7304a1
  title: "Surveillance for Acute Flaccid Myelitis - United States, 2018-2022"
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
- reference: PMID:38300829
  title: Surveillance for Acute Flaccid Myelitis - United States, 2018-2022.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: DOI:10.15585/mmwr.mm6931e3
  title: "<i>Vital Signs:</i> Clinical Characteristics of Patients with Confirmed Acute Flaccid Myelitis, United States, 2018"
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: DOI:10.3201/eid3003.231223
  title: Multimodal Surveillance Model for Enterovirus D68 Respiratory Disease and Acute Flaccid Myelitis among Children in Colorado, USA, 2022
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: DOI:10.1128/mbio.01058-23
  title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
- reference: PMID:37535397
  title: Contemporary enterovirus-D68 isolates infect human spinal cord organoids.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: DOI:10.1159/000535316
  title: A first case of acute flaccid myelitis related to enterovirus D-68 in Belgium
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: DOI:10.2106/JBJS.OA.23.00143
  title: Midterm Outcomes of Surgical Reconstruction and Spontaneous Recovery of Upper-Extremity Paralysis Following Acute Flaccid Myelitis
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
- reference: PMID:38774108
  title: Midterm Outcomes of Surgical Reconstruction and Spontaneous Recovery of Upper-Extremity Paralysis Following Acute Flaccid Myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: DOI:10.1016/j.pmr.2021.02.004
  title: Acute Flaccid Myelitis
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
- reference: PMID:37465770
  title: Acute Flaccid Myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: DOI:10.3390/children11091116
  title: Transcutaneous Spinal Cord Stimulation Enables Recovery of Walking in Children with Acute Flaccid Myelitis
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: DOI:10.1177/0883073820975230
  title: "Acute Flaccid Myelitis: A Multidisciplinary Protocol to Optimize Diagnosis and Evaluation"
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: DOI:10.3389/fmicb.2025.1698639
  title: Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-falcon.md
- reference: PMID:26720027
  title: Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:28231269
  title: A mouse model of paralytic myelitis caused by enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:28424289
  title: Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:28615421
  title: Outcomes of Colorado children with acute flaccid myelitis at 1 year.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:28968718
  title: Evaluating Treatment Efficacy in a Mouse Model of Enterovirus D68-Associated Paralytic Myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:29385753
  title: A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:30169722
  title: Acute flaccid myelitis-Clustering of polio-like illness in the tertiary care centre in Southern India.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:30503887
  title: A neonatal mouse model of Enterovirus D68 infection induces both interstitial pneumonia and acute flaccid myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:30530701
  title: Molecular basis for the acid-initiated uncoating of human enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:30575890
  title: Clinical, Radiologic, and Prognostic Features of Myelitis Associated With Myelin Oligodendrocyte Glycoprotein Autoantibody.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:30985511
  title: 'Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:31338675
  title: 'Acute flaccid myelitis and enterovirus D68: lessons from the past and present.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32178602
  title: Acute flaccid myelitis - has it gone unrecognised in Australian children?
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32192819
  title: Acute Flaccid Myelitis Among Hospitalized Children in Texas, 2016.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32492201
  title: 'Seroepidemiology of enterovirus D68 in a healthy population in Beijing, China, between 2012 and 2017: A retrospective study.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32677590
  title: 'Acute Flaccid Myelitis: A Single Pediatric Center Experience From 2014 to 2019.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32784424
  title: Mapping Attenuation Determinants in Enterovirus-D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32836175
  title: Cytokine biomarkers associated with clinical cases of acute flaccid myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:32951650
  title: 'The Utilization of Nerve Transfer for Reestablishing Shoulder Function in the Setting of Acute Flaccid Myelitis: A Single-Institution Review.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:33016189
  title: Recommendations for Therapy following Nerve Transfer for Children with Acute Flaccid Myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:33218883
  title: 'Acute flaccid myelitis outbreak through 2016-2018: A multicenter experience from Turkey.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:33388543
  title: Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:34170466
  title: Ectopic Expression of TRIM25 Restores RIG-I Expression and IFN Production Reduced by Multiple Enteroviruses 3C(pro).
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:34196272
  title: Respiratory and intestinal epithelial cells exhibit differential susceptibility and innate immune responses to contemporary EV-D68 isolates.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:34735423
  title: National Surveillance for Acute Flaccid Myelitis - United States, 2018-2020.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:34747551
  title: 'Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:36996587
  title: 'Pediatric acute flaccid myelitis: Evaluation of diagnostic criteria and differentiation from other causes of acute flaccid paralysis.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:37804367
  title: Insights into the molecular evolution of enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:37981447
  title: 'Nerve Transfer Surgery in Acute Flaccid Myelitis: Prognostic Factors, Long-Term Outcomes, Comparison With Natural History.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:38240591
  title: Enterovirus D68 3C protease antagonizes type I interferon signaling by cleaving signal transducer and activator of transcription 1.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:38405019
  title: 'A First Case of Acute Flaccid Myelitis Related to Enterovirus D68 in Belgium: Case Report.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:38547499
  title: Epidemiological and Clinical Insights into the Enterovirus D68 Upsurge in Europe 2021-2022 and Emergence of Novel B3-Derived Lineages, ENPEN Multicentre Study.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:38815052
  title: 'Acute Flaccid Myelitis: Mid-Term Clinical Course of Knee Extension Paralysis and Outcomes of Nerve Transfer.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:38869283
  title: VP1 is the primary determinant of neuropathogenesis in a mouse model of enterovirus D68 acute flaccid myelitis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39110777
  title: A self-amplifying RNA vaccine prevents enterovirus D68 infection and disease in preclinical models.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39246649
  title: Enterovirus-D68 - A Reemerging Non-Polio Enterovirus that Causes Severe Respiratory and Neurological Disease in Children.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39332429
  title: Global age-stratified seroprevalence of enterovirus D68: a systematic literature review.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39459875
  title: STING Orchestrates EV-D68 Replication and Immunometabolism within Viral-Induced Replication Organelles.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39657203
  title: 'Pediatric Patients With Acute Flaccid Myelitis: Long-term Respiratory and Neurologic Outcomes.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:39933731
  title: 'Phrenic Nerve Reconstruction in Pediatric Diaphragm Paralysis: Outcomes and Techniques.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40042308
  title: The structural protein VP3 of enterovirus D68 interacts with MAVS to inhibit the NF-κB signaling pathway.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40431685
  title: Return of the Biennial Circulation of Enterovirus D68 in Colorado Children in 2024 Following the Large 2022 Outbreak.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40444374
  title: 'Acute flaccid myelitis in Europe between 2016 and 2023: indicating the need for better registration.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40492725
  title: Enhanced genomic surveillance of enteroviruses reveals a surge in enterovirus D68 cases, the Johns Hopkins health system, Maryland, 2024.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40593720
  title: A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40622703
  title: 'West Nile Virus: A Review.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40661021
  title: '[Genomic characterization of a case of enterovirus D68 infection in a child from Tongzhou District, Beijing City].'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:40701343
  title: ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41138534
  title: 'Evolving Features of Acute Flaccid Myelitis After COVID-19: A Four-Case Series.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41175053
  title: 'Enterovirus D68: A Novel Inhibitor Reveals Underlying Molecular Mechanisms of Viral Entry and Uncoating.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41205525
  title: Matrine activates high xenophagy to inhibit enterovirus replication.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41210583
  title: mRNA vaccine expressing enterovirus D68 virus-like particles induces potent neutralizing antibodies and protects against infection.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41251130
  title: Efficacy and Safety of Plasmapheresis in Children With Acute Transverse or Flaccid Myelitis, and Guillain-Barré Syndrome.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41305500
  title: 'Spinal Cord Injury in Enterovirus D68 Infection: Mechanisms and Pathophysiology in a Mouse Model.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41352537
  title: Ubiquitin-specific protease 5 promotes EV-A71 replication by de-ubiquitinating MAVS and IRF3.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41410465
  title: 'Environmental surveillance reveals enterovirus diversity in Jinan, China: detection of types D68, A71, A76, B88, A90, and C99.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41467840
  title: 'Enterovirus D68 receptor usage: from static attachment to dynamic entry.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41483695
  title: 'Designing of a multi-epitope vaccine targeting enterovirus D68: An integrated immunoinformatic and reverse vaccinology approach.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41485562
  title: An orally available peptidomimetic with broad-spectrum antiviral activity targeting the enterovirus 2C helicase.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41600837
  title: 'Enterovirus D68 Sequence Variations and Pathogenicity: A Review.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41621223
  title: New fluoxetine analogues as anti-enterovirus agents targeting 2C protein.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41650963
  title: Mechanosensation promotes broad-spectrum antiviral defense through membrane remodeling.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41667472
  title: Rational design and in vivo validation of capsid inhibitors for enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41853773
  title: 'Enterovirus D68 in United States wastewater: a longitudinal surveillance study integrating climatic, demographic, and clinical data.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41868141
  title: 'Respiratory enterovirus D68: virology, clinical surveillance, host-pathogen interactions, and therapeutic prospects.'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41964219
  title: An RNA-to-RNA pipeline for rapid antiviral antibody development.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:41986256
  title: Circulation Patterns, Genetic Diversity, and Public Health Implications of Enterovirus D68, Europe, 2014-2024.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42018625
  title: Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42037410
  title: EV-D68 exploits clathrin-mediated endocytosis and compensatory macropinocytosis for cellular entry.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42037414
  title: Enterovirus D68 B3 clade strains are efficiently recovered from cDNA infectious clones in 293T cells and infect human spinal cord organoids.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42063851
  title: Rational Design of Capsid Protein VP1 Degraders to Overcome Pleconaril Resistance in Inhibiting Enterovirus D68.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42066114
  title: 'Enterovirus D68 and Acute Neurologic Outcomes: A Systematic Review and Meta-Analysis (2010-2025).'
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []
- reference: PMID:42086005
  title: Propagation and immunological characterization of three enterovirus D68 strains using serum-free HEK293A suspension cell culture.
  found_in:
  - Acute_Flaccid_Myelitis-deep-research-openscientist.md
  findings: []

📚