Autoimmune Encephalitis

Autoimmune MONDO:0020640 Pathograph 23 Show in embeddings browser Neurological Disease Autoimmune Disease

Autoimmune encephalitis (AE) is a heterogeneous group of inflammatory brain disorders with subacute cognitive, psychiatric, seizure, movement, sleep, autonomic, or consciousness syndromes. Some subtypes are mediated by antibodies to neuronal surface or synaptic antigens; others are associated with intracellular/onconeural antibodies and predominantly T-cell-mediated injury, and clinically probable seronegative AE also occurs. Antibody results therefore require syndrome, specimen, assay, and tumor-context interpretation. Early immunotherapy and treatment of an identified tumor are associated with better outcomes, but comparative treatment evidence remains limited.

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1
Definitions
7
Pathophys.
8
Phenotypes
2
Gaps
23
Pathograph
7
Medical Actions
7
Subtypes
6
Differentials
1
Datasets
3
Trials
2
Models
11
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC IMMUNE RHEUMATOLOGIC
📘

Definitions

1
Possible Autoimmune Encephalitis (Graus 2016)
Adult possible AE requires subacute progression in less than three months of working-memory deficit, altered mental status, or psychiatric symptoms; at least one new focal CNS finding, unexplained seizure, CSF pleocytosis, or MRI feature suggestive of encephalitis; and reasonable exclusion of other causes.
CASE_DEFINITION
Entry clinical syndrome
Core clinical characteristics
  • Memory impairment
  • Altered mental status
  • Psychosis
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"Subacute onset (rapid progression in fewer than than three months) of working memory de ficits (short-term memory loss), altered mental status (decreased level of consciousness, lethargy or personality changes), or psychiatric symptoms"
The 2024 consensus reproduces the Graus entry criterion and timing.
Show evidence (1 reference)
PMID:26906964 SUPPORT Other
"Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians."
Consensus guidance supports syndrome-based early assessment rather than waiting for antibodies.
◆

Subtypes

7
Anti-NMDA Receptor Encephalitis MONDO:0021081
GluN1-IgG-mediated encephalitis, often affecting children and young adults, with psychiatric/cognitive symptoms, seizures, dyskinesia, reduced consciousness, dysautonomia, or hypoventilation; ovarian teratoma and prior herpes simplex encephalitis are recognized triggers.
Show evidence (1 reference)
PMID:31326280 SUPPORT Other
"Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
Review evidence identifies the two established trigger contexts.
LGI1-Antibody Encephalitis MONDO:0015592
Usually an older-adult limbic encephalitis with seizures, faciobrachial dystonic seizures, cognitive impairment, and frequent hyponatremia.
Show evidence (1 reference)
DOI:10.3389/fneur.2021.674368 SUPPORT Human Clinical
"All patients presented with seizures at the initial consultation. Other common manifestations included cognitive dysfunction (82.2%), psychiatric disturbance (66.7%), sleep disorder (54.5%), and hyponatremia (66.7%)."
A primary cohort defines the principal LGI1 clinical associations.
CASPR2-Antibody Encephalitis MONDO:0017179
Encephalitis that can overlap with neuromyotonia or Morvan syndrome and can be tumor-associated, particularly with thymoma.
Show evidence (1 reference)
PMID:20663977 SUPPORT Human Clinical
"detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients."
The primary antibody-characterization cohort supports the tumor association.
GABAB-Receptor Encephalitis
Seizure-prominent limbic encephalitis associated with GABAB-receptor antibodies and, in a substantial subset, small-cell lung cancer.
Show evidence (1 reference)
PMID:19962348 SUPPORT Human Clinical
"GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies."
This primary case series defined the association; it did not alone prove pathogenicity.
AMPA-Receptor Encephalitis
GluA1/GluA2-antibody limbic encephalitis that is often paraneoplastic, treatment responsive, and relapse prone.
Show evidence (1 reference)
PMID:19338055 SUPPORT Human Clinical
"Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse."
The primary cohort supports association, clinical response, and relapse tendency.
Intracellular-Antigen/Paraneoplastic Encephalitis
Encephalitis associated with Hu, Ma2, CRMP5, amphiphysin, or related intracellular antigens; the antibodies are usually biomarkers of a tumor-driven cytotoxic T-cell response rather than demonstrated pathogenic effectors.
Show evidence (1 reference)
PMID:23250843 SUPPORT Other
"Patients with antibodies to intracellular neuronal antigens (onconeuronal antibodies: Hu, Ma2, amphiphysin, CV2/CRMP5) almost invariably have an underlying neoplasm (lung, testis, breast, etc.)"
Review evidence supports the classification and cancer association, not antibody pathogenicity.
Probable Seronegative Autoimmune Encephalitis
A clinically defined subgroup meeting high-specificity probable criteria despite absence of a well-characterized neural antibody; diagnosis requires objective inflammatory evidence and rigorous exclusion of alternatives.
Show evidence (1 reference)
PMID:26906964 SUPPORT Other
"Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy."
The consensus framework explicitly permits probability-based diagnosis before or without antibody confirmation.
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Discussions and Knowledge Gaps

2
Which AE antibodies are pathogenic effectors versus biomarkers of another immune mechanism?
INTERPRETATION OPEN antibody_association_vs_pathogenicity
Attached to
pathophysiology#Neural Antigen-Directed Autoimmunity
NMDAR and AMPAR antibodies have direct culture and transfer evidence; LGI1/CASPR2 effects vary by epitope/subclass; intracellular antibodies such as Hu are chiefly biomarkers of cytotoxic T-cell disease. A positive test must not be converted into a uniform antibody-causal edge.
Which acute, escalation, and maintenance regimens improve patient-centered outcomes by AE subtype?
KNOWLEDGE GAP OPEN comparative_treatment_evidence_gap
Attached to
treatments#Acute First-Line Immunotherapy treatments#Maintenance Immunosuppression
Most recommendations derive from retrospective evidence and expert consensus. CIELO, ExTINGUISH, and RADIA may address selected subtypes, but their protocols do not yet establish efficacy.
⚙

Pathophysiology

7
Neural Antigen-Directed Autoimmunity
AE comprises immune responses to extracellular neuronal surface/synaptic targets, intracellular/onconeural targets, and sometimes unidentified antigens. Antibody detection establishes association only; pathogenicity requires functional or transfer evidence.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
adaptive immune response GO:0002250 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased adaptive immune response (GO:0002250). GO:0002250 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Anti-GluN1 IgG-Mediated NMDAR Cluster Loss GluN1-directed autoimmunity can produce pathogenic receptor-cluster loss.
AMPAR Antibody-Mediated Synaptic Cluster Loss GluA1/GluA2-directed autoimmunity can reduce synaptic AMPAR clusters.
LGI1-ADAM22/23 Synaptic Signaling Disruption LGI1-directed autoimmunity can neutralize LGI1-ADAM22/23 signaling.
Intracellular-Antigen Cytotoxic T-Cell Injury Intracellular/onconeural antigen autoimmunity is linked to cytotoxic lymphocyte injury rather than antibody access to the target.
Show evidence (1 reference)
PMID:26906964 SUPPORT Other
"aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis"
Consensus evidence supports the heterogeneous syndrome framing; it does not imply a single causal pathway.
Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
In anti-NMDAR encephalitis, patient IgG binds extracellular GluN1 epitopes and selectively, concentration-dependently, and reversibly reduces postsynaptic NMDAR clusters without causing neuronal apoptosis in culture.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
glutamate receptor signaling pathway GO:0007215 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutamate receptor signaling pathway (GO:0007215). GO:0007215 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-CSF Hippocampal Neuron Culture Model PRIMARY CELL CULTURE Direct patient-antibody exposure tests receptor-cluster effects.
Chronic Patient-CSF Passive-Transfer Mouse Model OTHER Passive transfer tests whether patient CSF is sufficient for memory dysfunction.
Downstream
Reversible Synaptic Network Dysfunction Reduced synaptic NMDAR density alters glutamatergic transmission.
Show evidence (1 reference)
PMID:18851928 SUPPORT In Vitro
"adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration-dependent decrease of the cell-surface fraction of NMDA receptors"
This primary experiment supports pathogenic antibody action rather than association alone.
AMPAR Antibody-Mediated Synaptic Cluster Loss
AMPAR patient antibodies reduce GluA2-containing synaptic AMPAR clusters in cultured neurons, with reversal after antibody removal.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
glutamate receptor signaling pathway GO:0007215 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutamate receptor signaling pathway (GO:0007215). GO:0007215 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reversible Synaptic Network Dysfunction Loss of synaptic AMPAR localization impairs excitatory transmission.
Show evidence (1 reference)
PMID:19338055 SUPPORT In Vitro
"patients' antibodies alter the synaptic localization and number of AMPARs."
Functional evidence distinguishes pathogenicity from clinical association.
LGI1-ADAM22/23 Synaptic Signaling Disruption
LGI1 antibodies can disrupt LGI1 interactions with ADAM22/ADAM23 and alter synaptic organization or excitability. Epitope and IgG-subclass differences mean effects are not uniform across all patient antibodies.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reversible Synaptic Network Dysfunction Disrupted LGI1 trans-synaptic signaling changes neuronal excitability.
Show evidence (1 reference)
PMID:24227725 SUPPORT In Vitro
"LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons."
Primary functional evidence verifies both interaction neutralization and a downstream synaptic effect.
Intracellular-Antigen Cytotoxic T-Cell Injury
In onconeural/intracellular-antigen syndromes, the antibody usually marks a tumor-associated cellular immune response; cytotoxic T cells, rather than antibody binding to an inaccessible intracellular antigen, are considered the dominant neuronal-injury mechanism.
cytotoxic T cell CL:0000910 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cytotoxic T cell (CL:0000910). CL:0000910 is a cell type from the Cell Ontology.
T cell mediated cytotoxicity GO:0001913 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T cell mediated cytotoxicity (GO:0001913). GO:0001913 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Irreversible Inflammatory Neuronal Injury Antigen-directed cytotoxic lymphocytes injure neurons.
Show evidence (2 references)
PMID:22539258 SUPPORT Human Clinical
"We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases)"
Comparative tissue immunopathology provides purpose-built support beyond a single overlap case.
PMID:19338055 SUPPORT Human Clinical
"the autopsy confirmed prominent cytotoxic T-cell infiltrates in the limbic system."
Primary pathology supports T-cell-predominant injury in an intracellular-antigen overlap case.
Reversible Synaptic Network Dysfunction
Surface-antibody-mediated receptor or synaptic-protein effects converge on dysfunctional neuronal networks and can improve when antibody exposure ends.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Seizure Synaptic receptor disruption can create seizure-prone networks.
Cognitive Impairment Receptor and synaptic-protein effects impair learning and memory networks.
Psychiatric or Behavioral Disorder Synaptic receptor dysfunction can generate psychiatric and behavioral manifestations.
Movement Disorder NMDAR disruption can perturb motor circuits and produce dyskinesia.
Show evidence (1 reference)
PMID:18851928 SUPPORT In Vitro
"Patients’ antibodies did not change the concentrations of the postsynaptic protein PSD-95"
Selective receptor loss without generalized postsynaptic destruction supports reversible dysfunction.
Irreversible Inflammatory Neuronal Injury
T-cell-predominant intracellular-antigen encephalitis can cause destructive neuronal injury and generally responds less well than surface-antibody disease.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:19338055 SUPPORT Human Clinical
"the accompanying immune responses, particularly if associated with cytotoxic T-cell mechanisms, are more difficult to treat, or that the neuronal dysfunction is less reversible"
The authors cautiously infer lower reversibility from overlapping cytotoxic T-cell disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autoimmune Encephalitis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Metabolism 1
Hyponatremia FREQUENT HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fneur.2021.674368 SUPPORT Human Clinical
"Other common manifestations included cognitive dysfunction (82.2%), psychiatric disturbance (66.7%), sleep disorder (54.5%), and hyponatremia (66.7%)."
A primary LGI1 cohort supports subtype-specific frequency.
Nervous System 6
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1213532 SUPPORT Human Clinical
"The main clinical symptoms included seizures (74.8%)"
A 103-patient primary cohort supports the FREQUENT band for surface-antibody AE, not every subtype.
Psychiatric or Behavioral Disorder FREQUENT Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1213532 SUPPORT Human Clinical
"psychiatric and behavior disorders (66.0%)"
The cohort supports a grouped behavioral/psychiatric phenotype, not each individual psychiatric diagnosis.
Cognitive Impairment FREQUENT HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1213532 SUPPORT Human Clinical
"The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
A primary cohort supports the frequency band in its sampled antibody-positive population.
Movement Disorder OCCASIONAL Dyskinesia HP:0100660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyskinesia (HP:0100660). HP:0100660 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1213532 SUPPORT Human Clinical
"The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
The 26.2% estimate maps to OCCASIONAL, not FREQUENT.
Faciobrachial Dystonic Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
HPO lacks a specific FBDS term; the broader seizure term is used.
Show evidence (1 reference)
PMID:24014519 SUPPORT Human Clinical
"Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis."
A primary clinical study supports this subtype-specific clue.
EEG Slowing or Epileptiform Activity EEG abnormality HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19962348 SUPPORT Other
"EEG results were available from 12 patients: nine had temporal-lobe seizures, epileptiform discharges, or temporal-lobe slowing; two had generalised slowing; and one had no abnormalities."
A primary GABABR cohort supports the named EEG patterns; findings remain subtype-dependent and nonspecific.
Other 1
Disturbance of Consciousness FREQUENT Reduced consciousness HP:0004372 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced consciousness (HP:0004372). HP:0004372 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1213532 SUPPORT Human Clinical
"The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
The primary cohort supports a FREQUENT band.
💊

Medical Actions

7
Acute First-Line Immunotherapy
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: methylprednisolone NCIT:C647 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses methylprednisolone (NCIT:C647). NCIT:C647 is a therapeutic agent from the NCI Thesaurus.
High-dose corticosteroids plus IVIG or plasma exchange are commonly used promptly, with regimen individualized for severity and contraindications.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Suppresses inflammatory immune activity or modulates pathogenic antibodies.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis"
Consensus recommendation supports the regimen; comparative trial evidence is limited.
Plasma Exchange
Action: plasmapheresisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is plasmapheresis (NCIT:C15304). NCIT:C15304 is a clinical intervention from the NCI Thesaurus. Ontology label: Plasmapheresis NCIT:C15304
Removes circulating immunoglobulin and other plasma factors as an acute first-line option.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Reduces circulating antibody burden in antibody-mediated subtypes.
Show evidence (1 reference)
PMID:26559389 SUPPORT Other
"Most clinicians use first-line therapy (steroids, intravenous immunoglobulin, plasma exchange)"
Systematic review describes prevailing first-line practice.
Rituximab or Cyclophosphamide Escalation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus. cyclophosphamide CHEBI:4027 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclophosphamide (CHEBI:4027). CHEBI:4027 is a therapeutic agent from Chemical Entities of Biological Interest.
Second-line treatment for severe disease or inadequate response to first-line therapy.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Depletes B cells or broadly suppresses autoreactive lymphocytes.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"the second-line includes rituximab and/or cyclophosphamide"
Consensus recommendation; agent selection is not based on head-to-head randomized evidence.
Refractory-Disease Plasma-Cell or Cytokine-Directed Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: bortezomib NCIT:C1851 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses bortezomib (NCIT:C1851). NCIT:C1851 is a therapeutic agent from the NCI Thesaurus. tocilizumab NCIT:C84217 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tocilizumab (NCIT:C84217). NCIT:C84217 is a therapeutic agent from the NCI Thesaurus.
Bortezomib or tocilizumab may be considered in selected refractory disease by specialist teams; evidence is lower quality and risks are substantial.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Targets plasma-cell antibody production or IL-6 receptor signaling.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"third-line treatment options are bortezomib and tocilizumab."
Consensus supports specialist refractory use, not established equivalence or a universal sequence.
Tumor Resection or Oncologic Therapy
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Identify and promptly treat an associated neoplasm alongside immunotherapy.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Removes an antigenic tumor driver where present.
Show evidence (1 reference)
PMID:26559389 SUPPORT Other
"When present, tumours should be removed."
Review-level treatment recommendation is limited to tumor-associated disease.
Maintenance Immunosuppression
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus. mycophenolate mofetil NCIT:C1468 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (NCIT:C1468). NCIT:C1468 is a therapeutic agent from the NCI Thesaurus. azathioprine NCIT:C290 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses azathioprine (NCIT:C290). NCIT:C290 is a therapeutic agent from the NCI Thesaurus.
Maintenance rituximab, mycophenolate, or azathioprine may be considered for selected relapsing/high-risk cases; routine duration and benefit are not established across heterogeneous AE.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — Suppresses recurrent autoreactive immune activity.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"Data to guide long-term immunosuppression decisions in AIE are lacking."
The guideline documents the evidence gap; use must be individualized.
Efgartigimod (Investigational)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: efgartigimod alfa NCIT:C171817 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses efgartigimod alfa (NCIT:C171817). NCIT:C171817 is a therapeutic agent from the NCI Thesaurus.
FcRn inhibition is investigational in AE. A 15-patient retrospective series reported improvement with IgG reduction but explicitly did not establish causality; this is not evidence of standard efficacy.
Mechanism Target:
INHIBITS Neural Antigen-Directed Autoimmunity — FcRn blockade accelerates IgG catabolism.
Show evidence (1 reference)
PMID:42159021 SUPPORT Human Clinical
"However, no causal relationship was established between IgG reduction and clinical response. These findings need further validation."
Small uncontrolled retrospective evidence supports only investigational status.
🌍

Environmental Factors

3
Underlying Neoplasm
Tumor risk varies greatly by antibody; adult initial presentations require malignancy screening, and tumor treatment is part of disease management.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"All adult patients presenting with AIE should undergo screening for malignancy at the time of diagnosis."
This is a consensus recommendation across heterogeneous tumor risks.
Mechanism Target:
PREDISPOSES Neural Antigen-Directed Autoimmunity — Tumour risk in this entry varies so widely by antibody that no single route can be claimed across the syndrome. Graded below the checkpoint inhibitor link into this same node because that one has a sentence naming autoimmunity, while this one has a screening recommendation and a timing statistic.
Show evidence (2 references)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"All adult patients presenting with AIE should undergo screening for malignancy at the time of diagnosis."
Consensus recommendation that every adult presenting with the syndrome be screened for malignancy. It records what clinicians should do, not how a tumour reaches this node.
DOI:10.1017/cjn.2024.16 SUPPORT Other
"While paraneoplastic neurological disorders may precede a neoplasm diagnosis, a tumor is found within 1 year of presentation in >90% of cases with solid tumors"
Quantifies how tightly the tumour tracks the neurological presentation in paraneoplastic cases. Still a temporal association, which is why this stays partial.
Herpes Simplex Encephalitis
herpes simplex virus type 1 XCO:0000451 Experimental Conditions Ontology (XCO) Relation: this environmental factor is this exposure This environmental factor is herpes simplex virus type 1 (XCO:0000451). XCO:0000451 is an exposure from the Experimental Conditions Ontology.
Prior HSV encephalitis is an established trigger of secondary anti-NMDAR autoimmunity.
Show evidence (1 reference)
PMID:31326280 SUPPORT Other
"Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
The association is specific to post-HSE NMDAR autoimmunity, not every AE subtype.
Mechanism Target:
TRIGGERS Anti-GluN1 IgG-Mediated NMDAR Cluster Loss — Viral destruction of neurons releases synaptic antigen into a compartment the immune system can reach, and a GluN1-directed IgG response follows in a minority of survivors. Pointed at the NMDAR node rather than the general autoimmunity node because the association is specific to that antibody, which the entry's own evidence explanation already says.
Show evidence (1 reference)
PMID:31326280 SUPPORT Other
"Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
Names herpes simplex encephalitis as a known trigger of NMDAR autoimmunity specifically, which is the antibody this node carries.
Immune Checkpoint Inhibitor Exposure
immune checkpoint inhibitor exposure ECTO:9001737 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is immune checkpoint inhibitor exposure, annotated with exposure to antineoplastic agent (ECTO:9001737). ECTO:9001737 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Immune checkpoint inhibition can precipitate immune-mediated encephalitis as an adverse event.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"Immune checkpoint inhibitors (ICIs), used in the treatment of a growing number of malignancies, have also been identified as conferring increased risk for diverse neurological autoimmune complications, including AIE."
Guideline synthesis directly identifies immune checkpoint inhibition as an iatrogenic risk.
Mechanism Target:
PREDISPOSES Neural Antigen-Directed Autoimmunity — Releasing the checkpoint brakes on T cells lifts them against self antigens as well as tumour ones, which is the same adaptive-resistance machinery the immune_checkpoint_blockade module models from the tumour's side. Loss of peripheral tolerance is the intervening step. Recorded as predisposing rather than triggering because most treated patients never develop it.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"Immune checkpoint inhibitors (ICIs), used in the treatment of a growing number of malignancies, have also been identified as conferring increased risk for diverse neurological autoimmune complications, including AIE."
Guideline synthesis identifying checkpoint inhibitors as conferring increased risk of diverse neurological autoimmune complications, naming the autoimmunity this node holds rather than the syndrome alone.
🔬

Biochemical Markers

4
Paired Serum and CSF Neural-Antibody Testing (Subtype-dependent)
Context: Test both serum and CSF; interpret with phenotype and assay performance.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques."
Consensus guidance supports paired specimens and complementary methods.
CSF Pleocytosis (May be elevated)
Context: Supportive inflammatory finding; normal CSF does not exclude AE.
Show evidence (1 reference)
PMID:19962348 SUPPORT Human Clinical
"The most common CSF abnormality was lymphocytic pleocytosis in eight patients."
A primary GABABR cohort supports pleocytosis as a subtype finding; it is not universal across AE.
CSF Oligoclonal Bands and IgG Index (May be abnormal)
Context: Supportive but nonspecific intrathecal inflammation markers.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"All patients should be investigated using brain MRI, EEG, and CSF analysis, including the immunoglobulin G (IgG) index and oligoclonal bands (OCBs)."
Consensus guidance includes both in the baseline diagnostic workup.
CSF IL-6/STAT3 Multi-omics Signal (Increased candidate signal)
Context: Exploratory cross-sectional biomarker; not a proven causal pathway or validated clinical test.
Show evidence (1 reference)
PMID:42162799 SUPPORT Human Clinical
"Integrated multi-omics analysis validated these findings and identified several potential therapeutic targets for AIE, including the IL6-STAT3 axis."
Cross-sectional multi-omics nominates a candidate and cannot establish upstream causality.
🩻

Imaging Findings

3
Medial Temporal T2/FLAIR Hyperintensity
Unilateral or bilateral medial temporal T2/FLAIR hyperintensity supports autoimmune limbic encephalitis but is neither sensitive nor specific.
Mri Diagnostic
Abnormal hippocampus morphology HP:0025100 Human Phenotype Ontology (HP) hippocampal formation UBERON:0002421 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:19962348 SUPPORT Human Clinical
"Ten patients had unilateral or bilateral increases in medial temporal lobe FLAIR/T2 signal consistent with limbic encephalitis"
A primary GABABR cohort supports the subtype pattern, not universal AE frequency.
Normal or Nonspecific Brain MRI
MRI can be normal or show nonspecific abnormalities, particularly in anti-NMDAR encephalitis; a normal MRI does not exclude AE.
Mri
Show evidence (1 reference)
PMID:18851928 SUPPORT Human Clinical
"MRI findings are less predictable; only 55% of patients had increased FLAIR or T2 signal in one or several brain regions"
Primary cohort data show limited MRI sensitivity in anti-NMDAR disease.
Brain FDG-PET Abnormality
FDG-PET may be more sensitive than MRI and can reveal regional hypermetabolism or hypometabolism when MRI is unrevealing, but it must complement rather than replace other clinical and inflammatory evidence.
Pet
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"FDG-PET should not be used alone for diagnosis, rather to complement other evidence of AIE inflammation"
The guideline supports sensitivity and complementary use while rejecting stand-alone diagnosis.
📈

Progression

3
Subacute onset
Core cognitive, mental-status, psychiatric, seizure, or focal features progress over less than three months.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"Subacute onset (rapid progression in fewer than than three months)"
Consensus criteria define the onset window.
Acute treatment and early recovery
Treatment should begin promptly after reasonable infectious exclusion when clinical suspicion is high; recovery rate and tempo vary by subtype and severity.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"Treatment should be started within the first 4 weeks of symptoms."
This is a consensus timing recommendation, not randomized evidence.
Relapse or persistent sequelae
Relapse rates differ by antibody and cohort; objective new worsening after improvement or plateau should be distinguished from fluctuating sequelae, psychiatric disease, epilepsy, infection, and treatment complications.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"CASPR2 antibody encephalitis indicate relapse rates ranging from 10 to 41% and symptoms may be identical to the index episode"
Guideline synthesis supports a wide subtype-dependent range.
📊

Prevalence

2
Denmark, antibody-positive AE, 2019-2023
Annual Incidence 0.28 per 100,000 1–9 per 1,000,000
Nationwide centralized-testing estimate of 2.8 per million person-years; seronegative AE is outside this case frame.
Show evidence (1 reference)
PMID:42493607 SUPPORT Human Clinical
"The national average crude incidence rate (IR) in 2019-2023 was 2.8 cases per million person-years."
The reported rate converts to 0.28 per 100,000 person-years.
Guideline synthesis across AE ascertainment studies
Annual Incidence 0.2–0.8 per 100,000 1–9 per 1,000,000
Rates are per 100,000 person-years and vary with case definition and ascertainment.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"with an incidence of 0.2 – 0.8 per 100,000-person years."
Guideline synthesis supplies the range; this is not a new primary estimate.
🌍

Epidemiology

2
Danish neuronal-antibody AE incidence, 2019-2023
A nationwide centralized-testing cohort estimated a crude incidence of 2.8 cases per million person-years for antibody-positive AE in Denmark during 2019-2023; this excludes some seronegative disease and depends on ascertainment.
Show evidence (1 reference)
PMID:42493607 SUPPORT Human Clinical
"The national average crude incidence rate (IR) in 2019-2023 was 2.8 cases per million person-years."
This is a primary nationwide cohort estimate with a defined antibody-positive case frame.
Broad AE incidence range
Guideline synthesis estimates incidence at approximately 0.2-0.8 per 100,000 person-years, with ascertainment, antibody panels, and case definitions contributing to variation.
Show evidence (1 reference)
DOI:10.1017/cjn.2024.16 SUPPORT Other
"with an incidence of 0.2 – 0.8 per 100,000-person years."
This is a guideline-level synthesis, not a new primary estimate.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Autoimmune Encephalitis:

Infectious Encephalitis
Overlapping Features HSV and other infections can closely mimic AE and require urgent CSF PCR, cultures, and empiric antimicrobial management when indicated before or alongside immunotherapy.
Show evidence (1 reference)
DOI:10.1055/s-0044-1788586 SUPPORT Other
"Herpesvirus encephalitis should be ruled out with CSF polymerase chain reactions (PCRs)."
Consensus includes herpesvirus exclusion in CSF workup.
Primary Psychiatric Disorder
Overlapping Features Isolated psychiatric illness is a common mimic; seizures, dyskinesia, autonomic instability, catatonia, focal findings, CSF inflammation, or characteristic EEG/MRI increase concern for AE.
Show evidence (1 reference)
PMID:37582614 SUPPORT Other
"The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
A primary referral cohort identifies psychiatric disorders as a common mimic.
Noninflammatory Epilepsy or Status Epilepticus
Overlapping Features Seizures and postictal encephalopathy can mimic AE without autoimmune inflammation.
Show evidence (1 reference)
PMID:37582614 SUPPORT Human Clinical
"epilepsy with a noninflammatory cause (13%)"
A primary referral-cohort validation identifies noninflammatory epilepsy as a common mimic.
Neurodegenerative or Rapidly Progressive Dementia
Overlapping Features Prion and other neurodegenerative diseases can produce rapid cognitive, psychiatric, movement, EEG, or MRI abnormalities.
Show evidence (1 reference)
PMID:37582614 SUPPORT Human Clinical
"The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
A primary referral cohort quantifies this mimic category.
Toxic-Metabolic Encephalopathy
Overlapping Features Medication, substance, endocrine, electrolyte, hepatic, renal, and nutritional causes require targeted exclusion.
CNS Neoplasm, Stroke, or Other Neuroinflammatory Disease
Overlapping Features Tumor, lymphoma, vascular lesions, demyelinating disease, CNS vasculitis, and GFAP/MOG-associated disorders may overlap clinically or radiographically.
Show evidence (1 reference)
PMID:37582614 SUPPORT Human Clinical
"The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
The cohort supports both broad neuroinflammatory and CNS-neoplasm mimic categories; individual diagnoses require separate workup.
📊

Related Datasets

1
scRNAseq of CD8+ T cells from autoimmune encephalitis geo:GSE263666
Single-cell RNA sequencing in seven anti-Ri autoimmune encephalitis (AIE) patients and three controls showed that neuron-reactive CD8+ T cells are cytotoxic KIR+ CD8+ regulatory T cells. In Ri-AIE, these cells had reduced KIR and IKZF2 (Helios) expression, alongside activated TCR signaling and elevated TNF and IFNG. They also overexpressed TOX, linked to brain-infiltrating cytotoxicity. These findings suggest a loss of regulatory function in KIR+ CD8+ T cells contributes to Ri-AIE pathogenesis.
human SINGLE CELL RNA SEQ n=11
PMID:41022795
Identified by GEO DataSets index search for Autoimmune Encephalitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
🔬

Clinical Trials

3
NCT05503264 (CIELO) PHASE_III RECRUITING
Randomized double-blind placebo-controlled basket trial of satralizumab in NMDAR-IgG- or LGI1-IgG-positive encephalitis; no efficacy conclusion should be drawn before results.
Show evidence (1 reference)
clinicaltrials:NCT05503264 SUPPORT Human Clinical
"The purpose of this study is to assess the efficacy, safety, PK, and PD of satralizumab in participants with NMDAR and LGI1 encephalitis."
Registry evidence establishes trial design/status only.
ExTINGUISH (NCT04372615) PHASE_II ACTIVE_NOT_RECRUITING
Phase 2b randomized double-blind placebo-controlled inebilizumab trial in anti-NMDAR encephalitis; the 2025 publication is a protocol, not an efficacy report.
Show evidence (1 reference)
PMID:40625668 SUPPORT Human Clinical
"The ExTINGUISH trial is a multisite, phase 2B, randomized, double-blind, placebo-controlled trial"
Protocol publication establishes trial design and cannot support benefit.
NCT06867991 (RADIA) RECRUITING
Multicenter open-label randomized trial comparing ofatumumab followed by daratumumab, ofatumumab alone, and repeated IVIG/plasma exchange in severe AE, primarily anti-NMDAR encephalitis.
Show evidence (1 reference)
PMID:42293080 SUPPORT Human Clinical
"A total of 200 patients will be randomized at a 2:2:1 ratio into three groups."
Protocol evidence supports design only; results are not available.
🧫

Experimental Models

2
Patient-CSF Hippocampal Neuron Culture Model PRIMARY_CELL_CULTURE
Rat hippocampal neurons exposed to anti-NMDAR patient CSF/IgG model concentration-dependent, selective, reversible loss of surface and postsynaptic NMDAR clusters without apoptosis.
Organism
Norway rat NCBITaxon:10116 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Norway rat, annotated with Rattus norvegicus (NCBITaxon:10116). NCBITaxon:10116 is an organism from the NCBI Taxonomy.
Pathograph links
Anti-GluN1 IgG-Mediated NMDAR Cluster Loss Direct patient-antibody exposure tests receptor-cluster effects.
Findings
Patient IgG selectively and reversibly reduces postsynaptic NMDAR clusters.
"Together, these findings show that patients’ antibodies produce a selective and reversible decrease of NMDA-receptor clusters in postsynaptic dendrites."
Show evidence (1 reference)
PMID:18851928 SUPPORT In Vitro
"adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration-dependent decrease of the cell-surface fraction of NMDA receptors"
Primary culture experiment provides direct mechanistic evidence but does not reproduce the full syndrome.
Chronic Patient-CSF Passive-Transfer Mouse Model OTHER
Continuous intraventricular infusion of anti-NMDAR patient CSF produces memory impairment and brain-bound human antibody in mice. It models one antibody-mediated domain, not the full human psychiatric, autonomic, tumor, or T-cell spectrum of AE.
Organism
house mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in house mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Pathograph links
Anti-GluN1 IgG-Mediated NMDAR Cluster Loss Passive transfer tests whether patient CSF is sufficient for memory dysfunction.
Findings
Chronic patient-CSF exposure induced memory deficits in mice.
"chronic exposure to CSF from patients with anti-NMDAR encephalitis induces memory deficits in mice"
Show evidence (1 reference)
PMID:26616272 SUPPORT Model Organism
"Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test."
Passive transfer supports pathogenic sufficiency for a restricted phenotype.
{ }

Source YAML

click to show 
name: Autoimmune Encephalitis
creation_date: "2026-03-06T00:00:00Z"
category: Autoimmune
disease_term:
  preferred_term: autoimmune encephalitis
  term:
    id: MONDO:0020640
    label: autoimmune encephalitis
parents:
- Neurological Disease
- Autoimmune Disease
synonyms:
- Autoimmune inflammatory encephalitis
- AE
description: >-
  Autoimmune encephalitis (AE) is a heterogeneous group of inflammatory brain
  disorders with subacute cognitive, psychiatric, seizure, movement, sleep,
  autonomic, or consciousness syndromes. Some subtypes are mediated by
  antibodies to neuronal surface or synaptic antigens; others are associated
  with intracellular/onconeural antibodies and predominantly T-cell-mediated
  injury, and clinically probable seronegative AE also occurs. Antibody results
  therefore require syndrome, specimen, assay, and tumor-context interpretation.
  Early immunotherapy and treatment of an identified tumor are associated with
  better outcomes, but comparative treatment evidence remains limited.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:26906964
      reference_title: "A clinical approach to diagnosis of autoimmune encephalitis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis."
      explanation: The defining organ-system presentation is an inflammatory brain disorder.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:26906964
      reference_title: "A clinical approach to diagnosis of autoimmune encephalitis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders."
      explanation: The consensus paper explicitly frames the disorder and its biomarkers as autoimmune.
has_subtypes:
- name: Anti-NMDA Receptor Encephalitis
  subtype_term:
    preferred_term: anti-NMDA receptor encephalitis
    term:
      id: MONDO:0021081
      label: anti-NMDA receptor encephalitis
  description: >-
    GluN1-IgG-mediated encephalitis, often affecting children and young adults,
    with psychiatric/cognitive symptoms, seizures, dyskinesia, reduced
    consciousness, dysautonomia, or hypoventilation; ovarian teratoma and prior
    herpes simplex encephalitis are recognized triggers.
  evidence:
  - reference: PMID:31326280
    reference_title: "An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
    explanation: Review evidence identifies the two established trigger contexts.
- name: LGI1-Antibody Encephalitis
  subtype_term:
    preferred_term: limbic encephalitis with LGI1 antibodies
    term:
      id: MONDO:0015592
      label: limbic encephalitis with LGI1 antibodies
  description: >-
    Usually an older-adult limbic encephalitis with seizures, faciobrachial
    dystonic seizures, cognitive impairment, and frequent hyponatremia.
  evidence:
  - reference: DOI:10.3389/fneur.2021.674368
    reference_title: "Clinical Characteristics and Long-Term Prognosis of Anti-LGI1 Encephalitis: A Single-Center Cohort Study in Beijing, China"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented with seizures at the initial consultation. Other common manifestations included cognitive dysfunction (82.2%), psychiatric disturbance (66.7%), sleep disorder (54.5%), and hyponatremia (66.7%)."
    explanation: A primary cohort defines the principal LGI1 clinical associations.
- name: CASPR2-Antibody Encephalitis
  subtype_term:
    preferred_term: limbic encephalitis with caspr2 antibodies
    term:
      id: MONDO:0017179
      label: limbic encephalitis with caspr2 antibodies
  description: >-
    Encephalitis that can overlap with neuromyotonia or Morvan syndrome and can
    be tumor-associated, particularly with thymoma.
  evidence:
  - reference: PMID:20663977
    reference_title: "Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients."
    explanation: The primary antibody-characterization cohort supports the tumor association.
- name: GABAB-Receptor Encephalitis
  description: >-
    Seizure-prominent limbic encephalitis associated with GABAB-receptor
    antibodies and, in a substantial subset, small-cell lung cancer.
  evidence:
  - reference: PMID:19962348
    reference_title: "Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies."
    explanation: This primary case series defined the association; it did not alone prove pathogenicity.
- name: AMPA-Receptor Encephalitis
  description: >-
    GluA1/GluA2-antibody limbic encephalitis that is often paraneoplastic,
    treatment responsive, and relapse prone.
  evidence:
  - reference: PMID:19338055
    reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse."
    explanation: The primary cohort supports association, clinical response, and relapse tendency.
- name: Intracellular-Antigen/Paraneoplastic Encephalitis
  description: >-
    Encephalitis associated with Hu, Ma2, CRMP5, amphiphysin, or related
    intracellular antigens; the antibodies are usually biomarkers of a
    tumor-driven cytotoxic T-cell response rather than demonstrated pathogenic
    effectors.
  evidence:
  - reference: PMID:23250843
    reference_title: "Limbic encephalitis and related cortical syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with antibodies to intracellular neuronal antigens (onconeuronal antibodies: Hu, Ma2, amphiphysin, CV2/CRMP5) almost invariably have an underlying neoplasm (lung, testis, breast, etc.)"
    explanation: Review evidence supports the classification and cancer association, not antibody pathogenicity.
- name: Probable Seronegative Autoimmune Encephalitis
  description: >-
    A clinically defined subgroup meeting high-specificity probable criteria
    despite absence of a well-characterized neural antibody; diagnosis requires
    objective inflammatory evidence and rigorous exclusion of alternatives.
  evidence:
  - reference: PMID:26906964
    reference_title: "A clinical approach to diagnosis of autoimmune encephalitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy."
    explanation: The consensus framework explicitly permits probability-based diagnosis before or without antibody confirmation.
definitions:
- name: Possible Autoimmune Encephalitis (Graus 2016)
  definition_type: CASE_DEFINITION
  description: >-
    Adult possible AE requires subacute progression in less than three months of
    working-memory deficit, altered mental status, or psychiatric symptoms;
    at least one new focal CNS finding, unexplained seizure, CSF pleocytosis, or
    MRI feature suggestive of encephalitis; and reasonable exclusion of other causes.
  criteria_sets:
  - name: Entry clinical syndrome
    core_clinical_characteristics:
    - preferred_term: Memory impairment
      term:
        id: HP:0002354
        label: Memory impairment
    - preferred_term: Altered mental status
      term:
        id: HP:0011446
        label: Abnormal mental status
    - preferred_term: Psychosis
      term:
        id: HP:0000709
        label: Psychosis
    evidence:
    - reference: DOI:10.1055/s-0044-1788586
      reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Subacute onset (rapid progression in fewer than than three months) of working memory de ficits (short-term memory loss), altered mental status (decreased level of consciousness, lethargy or personality changes), or psychiatric symptoms"
      explanation: The 2024 consensus reproduces the Graus entry criterion and timing.
  evidence:
  - reference: PMID:26906964
    reference_title: "A clinical approach to diagnosis of autoimmune encephalitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians."
    explanation: Consensus guidance supports syndrome-based early assessment rather than waiting for antibodies.
prevalence:
- population: Denmark, antibody-positive AE, 2019-2023
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.28
  notes: >-
    Nationwide centralized-testing estimate of 2.8 per million person-years;
    seronegative AE is outside this case frame.
  evidence:
  - reference: PMID:42493607
    reference_title: "Fifteen years of autoimmune encephalitis in Denmark: incidence, epidemiology, and trends in treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The national average crude incidence rate (IR) in 2019-2023 was 2.8 cases per million person-years."
    explanation: The reported rate converts to 0.28 per 100,000 person-years.
- population: Guideline synthesis across AE ascertainment studies
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.2
  rate_high: 0.8
  notes: Rates are per 100,000 person-years and vary with case definition and ascertainment.
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "with an incidence of 0.2 – 0.8 per 100,000-person years."
    explanation: Guideline synthesis supplies the range; this is not a new primary estimate.
epidemiology:
- name: Danish neuronal-antibody AE incidence, 2019-2023
  description: >-
    A nationwide centralized-testing cohort estimated a crude incidence of 2.8
    cases per million person-years for antibody-positive AE in Denmark during
    2019-2023; this excludes some seronegative disease and depends on ascertainment.
  unit: cases per million person-years
  evidence:
  - reference: PMID:42493607
    reference_title: "Fifteen years of autoimmune encephalitis in Denmark: incidence, epidemiology, and trends in treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The national average crude incidence rate (IR) in 2019-2023 was 2.8 cases per million person-years."
    explanation: This is a primary nationwide cohort estimate with a defined antibody-positive case frame.
- name: Broad AE incidence range
  description: >-
    Guideline synthesis estimates incidence at approximately 0.2-0.8 per
    100,000 person-years, with ascertainment, antibody panels, and case
    definitions contributing to variation.
  unit: cases per 100000 person-years
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "with an incidence of 0.2 – 0.8 per 100,000-person years."
    explanation: This is a guideline-level synthesis, not a new primary estimate.
pathophysiology:
- name: Neural Antigen-Directed Autoimmunity
  description: >-
    AE comprises immune responses to extracellular neuronal surface/synaptic
    targets, intracellular/onconeural targets, and sometimes unidentified
    antigens. Antibody detection establishes association only; pathogenicity
    requires functional or transfer evidence.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: adaptive immune response
    modifier: INCREASED
    term:
      id: GO:0002250
      label: adaptive immune response
  downstream:
  - target: Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
    causal_link_type: DIRECT
    description: GluN1-directed autoimmunity can produce pathogenic receptor-cluster loss.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration-dependent decrease of the cell-surface fraction of NMDA receptors"
      explanation: Primary functional experiments support this subtype-specific route.
  - target: AMPAR Antibody-Mediated Synaptic Cluster Loss
    causal_link_type: DIRECT
    description: GluA1/GluA2-directed autoimmunity can reduce synaptic AMPAR clusters.
    evidence:
    - reference: PMID:19338055
      reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "patients' antibodies alter the synaptic localization and number of AMPARs."
      explanation: Primary culture evidence supports this subtype-specific route.
  - target: LGI1-ADAM22/23 Synaptic Signaling Disruption
    causal_link_type: DIRECT
    description: LGI1-directed autoimmunity can neutralize LGI1-ADAM22/23 signaling.
    evidence:
    - reference: PMID:24227725
      reference_title: "Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23"
      explanation: Primary mechanistic work supports the route.
  - target: Intracellular-Antigen Cytotoxic T-Cell Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Tumor or self-antigen presentation to cytotoxic T cells
    description: Intracellular/onconeural antigen autoimmunity is linked to cytotoxic lymphocyte injury rather than antibody access to the target.
    evidence:
    - reference: PMID:22539258
      reference_title: "Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens."
      explanation: Comparative immunopathology in 17 cases supports the intracellular-antigen route.
  evidence:
  - reference: PMID:26906964
    reference_title: "A clinical approach to diagnosis of autoimmune encephalitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis"
    explanation: Consensus evidence supports the heterogeneous syndrome framing; it does not imply a single causal pathway.
- name: Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
  description: >-
    In anti-NMDAR encephalitis, patient IgG binds extracellular GluN1 epitopes
    and selectively, concentration-dependently, and reversibly reduces
    postsynaptic NMDAR clusters without causing neuronal apoptosis in culture.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: glutamate receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  downstream:
  - target: Reversible Synaptic Network Dysfunction
    causal_link_type: DIRECT
    description: Reduced synaptic NMDAR density alters glutamatergic transmission.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together, these findings show that patients’ antibodies produce a selective and reversible decrease of NMDA-receptor clusters in postsynaptic dendrites."
      explanation: Primary neuronal-culture experiments directly support this edge.
  evidence:
  - reference: PMID:18851928
    reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration-dependent decrease of the cell-surface fraction of NMDA receptors"
    explanation: This primary experiment supports pathogenic antibody action rather than association alone.
- name: AMPAR Antibody-Mediated Synaptic Cluster Loss
  description: >-
    AMPAR patient antibodies reduce GluA2-containing synaptic AMPAR clusters in
    cultured neurons, with reversal after antibody removal.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: glutamate receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  downstream:
  - target: Reversible Synaptic Network Dysfunction
    causal_link_type: DIRECT
    description: Loss of synaptic AMPAR localization impairs excitatory transmission.
    evidence:
    - reference: PMID:19338055
      reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal."
      explanation: Primary culture data directly support the causal edge.
  evidence:
  - reference: PMID:19338055
    reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "patients' antibodies alter the synaptic localization and number of AMPARs."
    explanation: Functional evidence distinguishes pathogenicity from clinical association.
- name: LGI1-ADAM22/23 Synaptic Signaling Disruption
  description: >-
    LGI1 antibodies can disrupt LGI1 interactions with ADAM22/ADAM23 and alter
    synaptic organization or excitability. Epitope and IgG-subclass differences
    mean effects are not uniform across all patient antibodies.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    modifier: ABNORMAL
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  downstream:
  - target: Reversible Synaptic Network Dysfunction
    causal_link_type: DIRECT
    description: Disrupted LGI1 trans-synaptic signaling changes neuronal excitability.
    evidence:
    - reference: PMID:24227725
      reference_title: "Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23"
      explanation: Primary experiments support the interaction effect.
  evidence:
  - reference: PMID:24227725
    reference_title: "Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons."
    explanation: Primary functional evidence verifies both interaction neutralization and a downstream synaptic effect.
- name: Intracellular-Antigen Cytotoxic T-Cell Injury
  description: >-
    In onconeural/intracellular-antigen syndromes, the antibody usually marks a
    tumor-associated cellular immune response; cytotoxic T cells, rather than
    antibody binding to an inaccessible intracellular antigen, are considered
    the dominant neuronal-injury mechanism.
  cell_types:
  - preferred_term: cytotoxic T cell
    term:
      id: CL:0000910
      label: cytotoxic T cell
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    modifier: INCREASED
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  downstream:
  - target: Irreversible Inflammatory Neuronal Injury
    causal_link_type: DIRECT
    description: Antigen-directed cytotoxic lymphocytes injure neurons.
    evidence:
    - reference: PMID:19338055
      reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the autopsy confirmed prominent cytotoxic T-cell infiltrates in the limbic system."
      explanation: A CRMP5-overlap autopsy supports cytotoxic infiltration, but a single case cannot establish a universal mechanism.
  evidence:
  - reference: PMID:22539258
    reference_title: "Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases)"
    explanation: Comparative tissue immunopathology provides purpose-built support beyond a single overlap case.
  - reference: PMID:19338055
    reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the autopsy confirmed prominent cytotoxic T-cell infiltrates in the limbic system."
    explanation: Primary pathology supports T-cell-predominant injury in an intracellular-antigen overlap case.
- name: Reversible Synaptic Network Dysfunction
  description: >-
    Surface-antibody-mediated receptor or synaptic-protein effects converge on
    dysfunctional neuronal networks and can improve when antibody exposure ends.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: chemical synaptic transmission
    modifier: ABNORMAL
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered excitatory and inhibitory network balance
    description: Synaptic receptor disruption can create seizure-prone networks.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "During the first 3 weeks of symptom presentation, 76 patients had seizures."
      explanation: Clinical co-occurrence plus direct receptor-loss experiments support, but do not isolate, this path.
  - target: Cognitive Impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired synaptic plasticity in memory networks
    description: Receptor and synaptic-protein effects impair learning and memory networks.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This feature is compatible with disruption of the mechanisms of synaptic plasticity, thought to underlie learning and memory, in which the NMDA receptors play a key part."
      explanation: The authors connect NMDAR synaptic plasticity disruption to amnesia; umbrella generalization remains partial.
  - target: Psychiatric or Behavioral Disorder
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurotransmitter and circuit dysregulation
    description: Synaptic receptor dysfunction can generate psychiatric and behavioral manifestations.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "several NMDA-receptor antagonists such as MK801, ketamine, and phencyclidine cause symptoms similar to anti-NMDA-receptor encephalitis, including psychotic behaviour"
      explanation: Pharmacologic phenocopy supports a mechanistic connection in anti-NMDAR disease.
  - target: Movement Disorder
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dopaminergic circuit dysregulation
    description: NMDAR disruption can perturb motor circuits and produce dyskinesia.
    evidence:
    - reference: PMID:18851928
      reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "signs of involvement of dopaminergic pathways (rigidity, dystonia, orofacial movements, tremor)"
      explanation: Pharmacologic and clinical patterns support an indirect anti-NMDAR-specific route.
  evidence:
  - reference: PMID:18851928
    reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patients’ antibodies did not change the concentrations of the postsynaptic protein PSD-95"
    explanation: Selective receptor loss without generalized postsynaptic destruction supports reversible dysfunction.
- name: Irreversible Inflammatory Neuronal Injury
  description: >-
    T-cell-predominant intracellular-antigen encephalitis can cause destructive
    neuronal injury and generally responds less well than surface-antibody disease.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:19338055
    reference_title: "AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the accompanying immune responses, particularly if associated with cytotoxic T-cell mechanisms, are more difficult to treat, or that the neuronal dysfunction is less reversible"
    explanation: The authors cautiously infer lower reversibility from overlapping cytotoxic T-cell disease.
phenotypes:
- name: Seizure
  category: Neurologic
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: DOI:10.3389/fimmu.2023.1213532
    reference_title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical symptoms included seizures (74.8%)"
    explanation: A 103-patient primary cohort supports the FREQUENT band for surface-antibody AE, not every subtype.
- name: Psychiatric or Behavioral Disorder
  category: Psychiatric
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: DOI:10.3389/fimmu.2023.1213532
    reference_title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "psychiatric and behavior disorders (66.0%)"
    explanation: The cohort supports a grouped behavioral/psychiatric phenotype, not each individual psychiatric diagnosis.
- name: Cognitive Impairment
  category: Neurologic
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: DOI:10.3389/fimmu.2023.1213532
    reference_title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
    explanation: A primary cohort supports the frequency band in its sampled antibody-positive population.
- name: Disturbance of Consciousness
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Reduced consciousness
    term:
      id: HP:0004372
      label: Reduced consciousness
  evidence:
  - reference: DOI:10.3389/fimmu.2023.1213532
    reference_title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
    explanation: The primary cohort supports a FREQUENT band.
- name: Movement Disorder
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dyskinesia
    term:
      id: HP:0100660
      label: Dyskinesia
  evidence:
  - reference: DOI:10.3389/fimmu.2023.1213532
    reference_title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical symptoms included seizures (74.8%), psychiatric and behavior disorders (66.0%), cognitive deficits (51.5%), disturbances of consciousness (45.6%), and movement disorders/involuntary movements (26.2%)."
    explanation: The 26.2% estimate maps to OCCASIONAL, not FREQUENT.
- name: Faciobrachial Dystonic Seizures
  subtype: LGI1-Antibody Encephalitis
  category: Neurologic
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: HPO lacks a specific FBDS term; the broader seizure term is used.
  evidence:
  - reference: PMID:24014519
    reference_title: "Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis."
    explanation: A primary clinical study supports this subtype-specific clue.
- name: Hyponatremia
  subtype: LGI1-Antibody Encephalitis
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: DOI:10.3389/fneur.2021.674368
    reference_title: "Clinical Characteristics and Long-Term Prognosis of Anti-LGI1 Encephalitis: A Single-Center Cohort Study in Beijing, China"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common manifestations included cognitive dysfunction (82.2%), psychiatric disturbance (66.7%), sleep disorder (54.5%), and hyponatremia (66.7%)."
    explanation: A primary LGI1 cohort supports subtype-specific frequency.
- name: EEG Slowing or Epileptiform Activity
  category: Electrophysiologic
  diagnostic: true
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  electrophysiology:
    electrophysiology_modality: EEG
  evidence:
  - reference: PMID:19962348
    reference_title: "Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EEG results were available from 12 patients: nine had temporal-lobe seizures, epileptiform discharges, or temporal-lobe slowing; two had generalised slowing; and one had no abnormalities."
    explanation: A primary GABABR cohort supports the named EEG patterns; findings remain subtype-dependent and nonspecific.
biochemical:
- name: Paired Serum and CSF Neural-Antibody Testing
  presence: Subtype-dependent
  context: Test both serum and CSF; interpret with phenotype and assay performance.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques."
    explanation: Consensus guidance supports paired specimens and complementary methods.
- name: CSF Pleocytosis
  presence: May be elevated
  context: Supportive inflammatory finding; normal CSF does not exclude AE.
  evidence:
  - reference: PMID:19962348
    reference_title: "Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common CSF abnormality was lymphocytic pleocytosis in eight patients."
    explanation: A primary GABABR cohort supports pleocytosis as a subtype finding; it is not universal across AE.
- name: CSF Oligoclonal Bands and IgG Index
  presence: May be abnormal
  context: Supportive but nonspecific intrathecal inflammation markers.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All patients should be investigated using brain MRI, EEG, and CSF analysis, including the immunoglobulin G (IgG) index and oligoclonal bands (OCBs)."
    explanation: Consensus guidance includes both in the baseline diagnostic workup.
- name: CSF IL-6/STAT3 Multi-omics Signal
  presence: Increased candidate signal
  context: Exploratory cross-sectional biomarker; not a proven causal pathway or validated clinical test.
  evidence:
  - reference: PMID:42162799
    reference_title: "Multi-omics profiling of cerebrospinal fluid in autoimmune encephalitis: insights into pathogenesis and therapeutic targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Integrated multi-omics analysis validated these findings and identified several potential therapeutic targets for AIE, including the IL6-STAT3 axis."
    explanation: Cross-sectional multi-omics nominates a candidate and cannot establish upstream causality.
imaging_findings:
- name: Medial Temporal T2/FLAIR Hyperintensity
  modality: MRI
  diagnostic: true
  imaging_finding_term:
    preferred_term: Abnormal hippocampus morphology
    term:
      id: HP:0025100
      label: Abnormal hippocampus morphology
  located_in:
    preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  description: >-
    Unilateral or bilateral medial temporal T2/FLAIR hyperintensity supports
    autoimmune limbic encephalitis but is neither sensitive nor specific.
  evidence:
  - reference: PMID:19962348
    reference_title: "Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients had unilateral or bilateral increases in medial temporal lobe FLAIR/T2 signal consistent with limbic encephalitis"
    explanation: A primary GABABR cohort supports the subtype pattern, not universal AE frequency.
- name: Normal or Nonspecific Brain MRI
  modality: MRI
  diagnostic: false
  description: >-
    MRI can be normal or show nonspecific abnormalities, particularly in
    anti-NMDAR encephalitis; a normal MRI does not exclude AE.
  evidence:
  - reference: PMID:18851928
    reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI findings are less predictable; only 55% of patients had increased FLAIR or T2 signal in one or several brain regions"
    explanation: Primary cohort data show limited MRI sensitivity in anti-NMDAR disease.
- name: Brain FDG-PET Abnormality
  modality: PET
  diagnostic: false
  description: >-
    FDG-PET may be more sensitive than MRI and can reveal regional
    hypermetabolism or hypometabolism when MRI is unrevealing, but it must
    complement rather than replace other clinical and inflammatory evidence.
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FDG-PET should not be used alone for diagnosis, rather to complement other evidence of AIE inflammation"
    explanation: The guideline supports sensitivity and complementary use while rejecting stand-alone diagnosis.
environmental:
- name: Underlying Neoplasm
  influences_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Tumour risk in this entry varies so widely by antibody that no single
      route can be claimed across the syndrome. Graded below the checkpoint
      inhibitor link into this same node because that one has a sentence
      naming autoimmunity, while this one has a screening recommendation and a
      timing statistic.
    evidence:
    - reference: DOI:10.1017/cjn.2024.16
      reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "All adult patients presenting with AIE should undergo screening for malignancy at the time of diagnosis."
      explanation: >-
        Consensus recommendation that every adult presenting with the syndrome
        be screened for malignancy. It records what clinicians should do, not
        how a tumour reaches this node.
    - reference: DOI:10.1017/cjn.2024.16
      reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "While paraneoplastic neurological disorders may precede a neoplasm diagnosis, a tumor is found within 1 year of presentation in >90% of cases with solid tumors"
      explanation: >-
        Quantifies how tightly the tumour tracks the neurological presentation
        in paraneoplastic cases. Still a temporal association, which is why
        this stays partial.
  description: >-
    Tumor risk varies greatly by antibody; adult initial presentations require
    malignancy screening, and tumor treatment is part of disease management.
  effect: Triggers or sustains paraneoplastic autoimmunity
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All adult patients presenting with AIE should undergo screening for malignancy at the time of diagnosis."
    explanation: This is a consensus recommendation across heterogeneous tumor risks.
- name: Herpes Simplex Encephalitis
  exposure_term:
    preferred_term: herpes simplex virus type 1
    term:
      id: XCO:0000451
      label: Herpes simplex virus type 1
  influences_mechanisms:
  - target: Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Viral destruction of neurons releases synaptic antigen into a
      compartment the immune system can reach, and a GluN1-directed IgG
      response follows in a minority of survivors. Pointed at the NMDAR node
      rather than the general autoimmunity node because the association is
      specific to that antibody, which the entry's own evidence explanation
      already says.
    evidence:
    - reference: PMID:31326280
      reference_title: "An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
      explanation: >-
        Names herpes simplex encephalitis as a known trigger of NMDAR
        autoimmunity specifically, which is the antibody this node carries.
  description: Prior HSV encephalitis is an established trigger of secondary anti-NMDAR autoimmunity.
  effect: Post-infectious trigger
  evidence:
  - reference: PMID:31326280
    reference_title: "An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity."
    explanation: The association is specific to post-HSE NMDAR autoimmunity, not every AE subtype.
- name: Immune Checkpoint Inhibitor Exposure
  exposure_term:
    preferred_term: immune checkpoint inhibitor exposure
    term:
      id: ECTO:9001737
      label: exposure to antineoplastic agent
  influences_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Releasing the checkpoint brakes on T cells lifts them against self
      antigens as well as tumour ones, which is the same adaptive-resistance
      machinery the immune_checkpoint_blockade module models from the tumour's
      side. Loss of peripheral tolerance is the intervening step. Recorded as
      predisposing rather than triggering because most treated patients never
      develop it.
    evidence:
    - reference: DOI:10.1017/cjn.2024.16
      reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Immune checkpoint inhibitors (ICIs), used in the treatment of a growing number of malignancies, have also been identified as conferring increased risk for diverse neurological autoimmune complications, including AIE."
      explanation: >-
        Guideline synthesis identifying checkpoint inhibitors as conferring
        increased risk of diverse neurological autoimmune complications,
        naming the autoimmunity this node holds rather than the syndrome
        alone.
  description: Immune checkpoint inhibition can precipitate immune-mediated encephalitis as an adverse event.
  effect: Iatrogenic immune trigger
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Immune checkpoint inhibitors (ICIs), used in the treatment of a growing number of malignancies, have also been identified as conferring increased risk for diverse neurological autoimmune complications, including AIE."
    explanation: Guideline synthesis directly identifies immune checkpoint inhibition as an iatrogenic risk.
progression:
- phase: Subacute onset
  notes: Core cognitive, mental-status, psychiatric, seizure, or focal features progress over less than three months.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Subacute onset (rapid progression in fewer than than three months)"
    explanation: Consensus criteria define the onset window.
- phase: Acute treatment and early recovery
  notes: >-
    Treatment should begin promptly after reasonable infectious exclusion when
    clinical suspicion is high; recovery rate and tempo vary by subtype and severity.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment should be started within the first 4 weeks of symptoms."
    explanation: This is a consensus timing recommendation, not randomized evidence.
- phase: Relapse or persistent sequelae
  notes: >-
    Relapse rates differ by antibody and cohort; objective new worsening after
    improvement or plateau should be distinguished from fluctuating sequelae,
    psychiatric disease, epilepsy, infection, and treatment complications.
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CASPR2 antibody encephalitis indicate relapse rates ranging from 10 to 41% and symptoms may be identical to the index episode"
    explanation: Guideline synthesis supports a wide subtype-dependent range.
treatments:
- name: Acute First-Line Immunotherapy
  description: >-
    High-dose corticosteroids plus IVIG or plasma exchange are commonly used
    promptly, with regimen individualized for severity and contraindications.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: NCIT:C647
        label: Methylprednisolone
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Suppresses inflammatory immune activity or modulates pathogenic antibodies.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis"
    explanation: Consensus recommendation supports the regimen; comparative trial evidence is limited.
- name: Plasma Exchange
  description: Removes circulating immunoglobulin and other plasma factors as an acute first-line option.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Reduces circulating antibody burden in antibody-mediated subtypes.
  evidence:
  - reference: PMID:26559389
    reference_title: "Immune therapy in autoimmune encephalitis: a systematic review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most clinicians use first-line therapy (steroids, intravenous immunoglobulin, plasma exchange)"
    explanation: Systematic review describes prevailing first-line practice.
- name: Rituximab or Cyclophosphamide Escalation
  description: Second-line treatment for severe disease or inadequate response to first-line therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Depletes B cells or broadly suppresses autoreactive lymphocytes.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the second-line includes rituximab and/or cyclophosphamide"
    explanation: Consensus recommendation; agent selection is not based on head-to-head randomized evidence.
- name: Refractory-Disease Plasma-Cell or Cytokine-Directed Therapy
  description: >-
    Bortezomib or tocilizumab may be considered in selected refractory disease
    by specialist teams; evidence is lower quality and risks are substantial.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bortezomib
      term:
        id: NCIT:C1851
        label: Bortezomib
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Targets plasma-cell antibody production or IL-6 receptor signaling.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "third-line treatment options are bortezomib and tocilizumab."
    explanation: Consensus supports specialist refractory use, not established equivalence or a universal sequence.
- name: Tumor Resection or Oncologic Therapy
  description: Identify and promptly treat an associated neoplasm alongside immunotherapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Removes an antigenic tumor driver where present.
  evidence:
  - reference: PMID:26559389
    reference_title: "Immune therapy in autoimmune encephalitis: a systematic review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When present, tumours should be removed."
    explanation: Review-level treatment recommendation is limited to tumor-associated disease.
- name: Maintenance Immunosuppression
  description: >-
    Maintenance rituximab, mycophenolate, or azathioprine may be considered for
    selected relapsing/high-risk cases; routine duration and benefit are not
    established across heterogeneous AE.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: mycophenolate mofetil
      term:
        id: NCIT:C1468
        label: Mycophenolate Mofetil
    - preferred_term: azathioprine
      term:
        id: NCIT:C290
        label: Azathioprine
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: Suppresses recurrent autoreactive immune activity.
  evidence:
  - reference: DOI:10.1017/cjn.2024.16
    reference_title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Data to guide long-term immunosuppression decisions in AIE are lacking."
    explanation: The guideline documents the evidence gap; use must be individualized.
- name: Efgartigimod (Investigational)
  description: >-
    FcRn inhibition is investigational in AE. A 15-patient retrospective series
    reported improvement with IgG reduction but explicitly did not establish
    causality; this is not evidence of standard efficacy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: efgartigimod alfa
      term:
        id: NCIT:C171817
        label: Efgartigimod Alfa
  target_mechanisms:
  - target: Neural Antigen-Directed Autoimmunity
    treatment_effect: INHIBITS
    description: FcRn blockade accelerates IgG catabolism.
  evidence:
  - reference: PMID:42159021
    reference_title: "The Clinical Efficacy and Safety of Efgartigimod in the Treatment of Autoimmune Encephalitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, no causal relationship was established between IgG reduction and clinical response. These findings need further validation."
    explanation: Small uncontrolled retrospective evidence supports only investigational status.
differential_diagnoses:
- name: Infectious Encephalitis
  description: >-
    HSV and other infections can closely mimic AE and require urgent CSF PCR,
    cultures, and empiric antimicrobial management when indicated before or
    alongside immunotherapy.
  evidence:
  - reference: DOI:10.1055/s-0044-1788586
    reference_title: Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Herpesvirus encephalitis should be ruled out with CSF polymerase chain reactions (PCRs)."
    explanation: Consensus includes herpesvirus exclusion in CSF workup.
- name: Primary Psychiatric Disorder
  description: >-
    Isolated psychiatric illness is a common mimic; seizures, dyskinesia,
    autonomic instability, catatonia, focal findings, CSF inflammation, or
    characteristic EEG/MRI increase concern for AE.
  evidence:
  - reference: PMID:37582614
    reference_title: "Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
    explanation: A primary referral cohort identifies psychiatric disorders as a common mimic.
- name: Noninflammatory Epilepsy or Status Epilepticus
  description: Seizures and postictal encephalopathy can mimic AE without autoimmune inflammation.
  evidence:
  - reference: PMID:37582614
    reference_title: "Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy with a noninflammatory cause (13%)"
    explanation: A primary referral-cohort validation identifies noninflammatory epilepsy as a common mimic.
- name: Neurodegenerative or Rapidly Progressive Dementia
  description: Prion and other neurodegenerative diseases can produce rapid cognitive, psychiatric, movement, EEG, or MRI abnormalities.
  evidence:
  - reference: PMID:37582614
    reference_title: "Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
    explanation: A primary referral cohort quantifies this mimic category.
- name: Toxic-Metabolic Encephalopathy
  description: Medication, substance, endocrine, electrolyte, hepatic, renal, and nutritional causes require targeted exclusion.
- name: CNS Neoplasm, Stroke, or Other Neuroinflammatory Disease
  description: >-
    Tumor, lymphoma, vascular lesions, demyelinating disease, CNS vasculitis,
    and GFAP/MOG-associated disorders may overlap clinically or radiographically.
  evidence:
  - reference: PMID:37582614
    reference_title: "Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%)."
    explanation: The cohort supports both broad neuroinflammatory and CNS-neoplasm mimic categories; individual diagnoses require separate workup.
experimental_models:
- name: Patient-CSF Hippocampal Neuron Culture Model
  description: >-
    Rat hippocampal neurons exposed to anti-NMDAR patient CSF/IgG model
    concentration-dependent, selective, reversible loss of surface and
    postsynaptic NMDAR clusters without apoptosis.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Norway rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  modeled_mechanisms:
  - target: Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
    description: Direct patient-antibody exposure tests receptor-cluster effects.
  findings:
  - statement: Patient IgG selectively and reversibly reduces postsynaptic NMDAR clusters.
    supporting_text: "Together, these findings show that patients’ antibodies produce a selective and reversible decrease of NMDA-receptor clusters in postsynaptic dendrites."
  evidence:
  - reference: PMID:18851928
    reference_title: "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration-dependent decrease of the cell-surface fraction of NMDA receptors"
    explanation: Primary culture experiment provides direct mechanistic evidence but does not reproduce the full syndrome.
- name: Chronic Patient-CSF Passive-Transfer Mouse Model
  description: >-
    Continuous intraventricular infusion of anti-NMDAR patient CSF produces
    memory impairment and brain-bound human antibody in mice. It models one
    antibody-mediated domain, not the full human psychiatric, autonomic, tumor,
    or T-cell spectrum of AE.
  experimental_model_type: OTHER
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: Anti-GluN1 IgG-Mediated NMDAR Cluster Loss
    description: Passive transfer tests whether patient CSF is sufficient for memory dysfunction.
  findings:
  - statement: Chronic patient-CSF exposure induced memory deficits in mice.
    supporting_text: "chronic exposure to CSF from patients with anti-NMDAR encephalitis induces memory deficits in mice"
  evidence:
  - reference: PMID:26616272
    reference_title: "Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test."
    explanation: Passive transfer supports pathogenic sufficiency for a restricted phenotype.
clinical_trials:
- name: NCT05503264 (CIELO)
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Randomized double-blind placebo-controlled basket trial of satralizumab in
    NMDAR-IgG- or LGI1-IgG-positive encephalitis; no efficacy conclusion should
    be drawn before results.
  evidence:
  - reference: clinicaltrials:NCT05503264
    reference_title: "A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Basket Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Satralizumab in Patients With Anti-N-methyl-D-aspartic Acid Receptor (NMDAR) or Anti-leucine-rich Glioma-inactivated 1 (LGI1) Encephalitis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to assess the efficacy, safety, PK, and PD of satralizumab in participants with NMDAR and LGI1 encephalitis."
    explanation: Registry evidence establishes trial design/status only.
- name: ExTINGUISH (NCT04372615)
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Phase 2b randomized double-blind placebo-controlled inebilizumab trial in
    anti-NMDAR encephalitis; the 2025 publication is a protocol, not an efficacy report.
  evidence:
  - reference: PMID:40625668
    reference_title: "A Phase-2B Double-Blind Randomized International Prospective Trial of Inebilizumab in NMDAR Encephalitis: The ExTINGUISH Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ExTINGUISH trial is a multisite, phase 2B, randomized, double-blind, placebo-controlled trial"
    explanation: Protocol publication establishes trial design and cannot support benefit.
- name: NCT06867991 (RADIA)
  status: RECRUITING
  description: >-
    Multicenter open-label randomized trial comparing ofatumumab followed by
    daratumumab, ofatumumab alone, and repeated IVIG/plasma exchange in severe
    AE, primarily anti-NMDAR encephalitis.
  evidence:
  - reference: PMID:42293080
    reference_title: "Safety and efficacy of combined B-cell depleting therapy and daratumumab in patients with autoimmune encephalitis (RADIA): study protocol for a multicenter, randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 200 patients will be randomized at a 2:2:1 ratio into three groups."
    explanation: Protocol evidence supports design only; results are not available.
datasets:
- accession: geo:GSE263666
  title: scRNAseq of CD8+ T cells from autoimmune encephalitis
  description: Single-cell RNA sequencing in seven anti-Ri autoimmune encephalitis (AIE) patients and three controls showed that neuron-reactive CD8+ T cells are cytotoxic KIR+ CD8+ regulatory T cells. In Ri-AIE, these cells had reduced KIR and IKZF2 (Helios) expression, alongside activated TCR signaling and elevated TNF and IFNG. They also overexpressed TOX, linked to brain-infiltrating cytotoxicity. These findings suggest a loss of regulatory function in KIR+ CD8+ T cells contributes to Ri-AIE pathogenesis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 11
  publication: PMID:41022795
  notes: Identified by GEO DataSets index search for Autoimmune Encephalitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
notes: >-
  Publication-readiness review through 2026-08-05: evidence remains dominated by
  retrospective cohorts, case series, consensus guidance, and subtype-specific
  mechanistic experiments; umbrella-level frequencies must not be generalized
  across antibodies. D2P audit dispositions (49/49): ACCEPTED as modeled clinical
  features—HP:0000708 atypical behavior, HP:0001289 confusion (represented by
  HP:0004372), HP:0002902 hyponatremia (LGI1 context), HP:0010532 paroxysmal
  vertigo was REJECTED (not a defining AE feature), HP:0001254 lethargy REJECTED,
  HP:0002315 headache REJECTED, HP:0002017 nausea/vomiting REJECTED,
  HP:0003470 paralysis REJECTED, HP:0010843 EEG focal slowing and HP:6001115 EEG
  temporal slowing ACCEPTED under the broader EEG-abnormality record,
  HP:0012229 CSF pleocytosis ACCEPTED as a biochemical/supportive finding,
  HP:6000397 CSF oligoclonal IgG bands and HP:0002922 increased CSF protein
  ACCEPTED as supportive CSF findings (protein retained in narrative scope, not a
  separate poorly specific record), HP:0012658 abnormal brain FDG-PET ACCEPTED
  as an imaging finding, HP:0002500 abnormal cerebral white-matter morphology
  REJECTED as nonspecific at umbrella level, HP:0006846 acute encephalopathy
  ACCEPTED through the case definition, HP:0000739 anxiety, HP:0000716
  depression, HP:0000737 irritability, and HP:0000853 goiter REJECTED as
  insufficiently specific standalone umbrella phenotypes, HP:0009102 anterior
  open-bite malocclusion, HP:0000872 Hashimoto thyroiditis, HP:0000821
  hypothyroidism, HP:0002721 immunodeficiency, HP:0001974 increased leukocytes,
  HP:0001873 thrombocytopenia, and HP:0005991 limited neck flexion REJECTED as
  contamination/nonspecific comorbidity; HP:0002181 cerebral edema,
  HP:0005318 cerebral vasculitis, HP:0100836 CNS malignant neoplasm, and
  HP:0001268 mental deterioration REJECTED as alternative pathology or overly
  nonspecific; HP:0002383 infectious encephalitis ACCEPTED only as a differential,
  never a phenotype. Antibody terms HP:5000005 anti-CASPR2, HP:5000010
  anti-GABABR, HP:5000016 anti-Hu, and HP:5000020 anti-LGI1 were ACCEPTED as
  subtype/biomarker associations, not phenotypes or proof of pathogenicity. The
  six unlinked local terms were dispositioned as follows: autonomic dysfunction
  REJECTED from the heterogeneous umbrella phenotype list for lack of a valid
  frequency source; dyskinesia ACCEPTED as movement disorder; memory impairment
  ACCEPTED as cognitive impairment; psychosis ACCEPTED only within the grouped
  psychiatric/behavioral phenotype; recurrent fever REJECTED because the source
  term/polarity was wrong and prodromal fever is nonspecific; seizure ACCEPTED.
  Broader matches HP:0012332 abnormal autonomic physiology was REJECTED at
  umbrella level but remains subtype-relevant; HP:0007359 focal seizure,
  HP:0002197 generalized seizure, and HP:0002133 status epilepticus were
  CONSOLIDATED under seizure because the umbrella cohort did not justify separate
  frequencies; HP:0033687 short-term memory impairment was CONSOLIDATED under
  cognitive impairment. No unsupported edges were added to increase connectivity.
references:
- reference: DOI:10.1017/cjn.2024.16
  title: "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults"
  found_in:
  - Autoimmune_Encephalitis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1055/s-0044-1788586
  title: "Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations"
  found_in:
  - Autoimmune_Encephalitis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fimmu.2023.1213532
  title: "Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china"
  found_in:
  - Autoimmune_Encephalitis-deep-research-falcon.md
  findings: []
- reference: PMID:42493607
  title: "Fifteen years of autoimmune encephalitis in Denmark: incidence, epidemiology, and trends in treatment."
  findings: []
- reference: PMID:42159021
  title: "The Clinical Efficacy and Safety of Efgartigimod in the Treatment of Autoimmune Encephalitis."
  findings: []
- reference: PMID:42293080
  title: "Safety and efficacy of combined B-cell depleting therapy and daratumumab in patients with autoimmune encephalitis (RADIA): study protocol for a multicenter, randomized trial."
  findings: []
- reference: PMID:40625668
  title: "A Phase-2B Double-Blind Randomized International Prospective Trial of Inebilizumab in NMDAR Encephalitis: The ExTINGUISH Trial."
  findings: []
- reference: PMID:26616272
  title: "Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis."
  findings: []
- reference: PMID:37582614
  title: "Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria."
  findings: []
- reference: PMID:24227725
  title: "Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors."
  findings: []
- reference: PMID:22539258
  title: "Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis."
  findings: []
discussions:
- discussion_id: antibody_association_vs_pathogenicity
  prompt: Which AE antibodies are pathogenic effectors versus biomarkers of another immune mechanism?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Neural Antigen-Directed Autoimmunity
  rationale: >-
    NMDAR and AMPAR antibodies have direct culture and transfer evidence;
    LGI1/CASPR2 effects vary by epitope/subclass; intracellular antibodies such
    as Hu are chiefly biomarkers of cytotoxic T-cell disease. A positive test
    must not be converted into a uniform antibody-causal edge.
- discussion_id: comparative_treatment_evidence_gap
  prompt: Which acute, escalation, and maintenance regimens improve patient-centered outcomes by AE subtype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Acute First-Line Immunotherapy
  - treatments#Maintenance Immunosuppression
  rationale: >-
    Most recommendations derive from retrospective evidence and expert
    consensus. CIELO, ExTINGUISH, and RADIA may address selected subtypes, but
    their protocols do not yet establish efficacy.
📚

References & Deep Research

References

11
DOI:10.1017/cjn.2024.16
Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults
No top-level findings curated for this source.
DOI:10.1055/s-0044-1788586
Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations
No top-level findings curated for this source.
DOI:10.3389/fimmu.2023.1213532
Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china
No top-level findings curated for this source.
PMID:42493607
Fifteen years of autoimmune encephalitis in Denmark: incidence, epidemiology, and trends in treatment.
No top-level findings curated for this source.
PMID:42159021
The Clinical Efficacy and Safety of Efgartigimod in the Treatment of Autoimmune Encephalitis.
No top-level findings curated for this source.
PMID:42293080
Safety and efficacy of combined B-cell depleting therapy and daratumumab in patients with autoimmune encephalitis (RADIA): study protocol for a multicenter, randomized trial.
No top-level findings curated for this source.
PMID:40625668
A Phase-2B Double-Blind Randomized International Prospective Trial of Inebilizumab in NMDAR Encephalitis: The ExTINGUISH Trial.
No top-level findings curated for this source.
PMID:26616272
Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis.
No top-level findings curated for this source.
PMID:37582614
Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria.
No top-level findings curated for this source.
PMID:24227725
Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors.
No top-level findings curated for this source.
PMID:22539258
Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Expert opinion & analysis (from authoritative sources)
Edison Scientific Literature 26 citations 2026-05-08T07:56:22.157353

1. Disease Information

1.1 Overview (current understanding)

Autoimmune encephalitis (AE; also written “autoimmune inflammatory encephalitis”, “autoimmune encephalopathy”, or “antibody-mediated encephalitis” depending on context) is a group of immune-mediated inflammatory brain disorders that typically present subacutely with neuropsychiatric symptoms, cognitive dysfunction, seizures, movement disorders, or altered level of consciousness, and are frequently associated with autoantibodies to neuronal cell-surface/synaptic or (in paraneoplastic neurologic syndromes) intracellular neuronal antigens. In a large real-world validation study, AE is described as being “associated with neuronal autoantibodies against extracellular antigens, which are directly pathogenic.” (steenhoven2023mimicsofautoimmune pages 1-2)

A practical case-definition used in modern guidelines is the 2016 Graus clinical criteria framework, which classifies patients as possible/probable/definite AE based on a subacute encephalopathy plus supportive MRI/CSF/EEG features, and then confirmation with syndrome-specific features and/or neural-specific antibody positivity. (orozco2023autoimmuneencephalitiscriteria pages 1-3, dutra2024brazilianconsensusrecommendations pages 4-5)

1.2 Key identifiers (knowledge-base fields)

Within the evidence corpus retrieved for this run, explicit mappings to MONDO, Orphanet, MeSH, and ICD-10/ICD-11 identifiers for “autoimmune encephalitis” were not available; therefore these identifiers cannot be reliably populated from the cited sources here.

1.3 Common synonyms / alternative names (usage)

Commonly used terms in the literature captured in this run include: - Autoimmune encephalitis (AE) / Autoimmune inflammatory encephalitis (AIE) (dutra2024brazilianconsensusrecommendations pages 1-2) - Antibody-associated encephalitis / antibody-mediated encephalitis (steenhoven2023mimicsofautoimmune pages 1-2, kerstens2024autoimmuneencephalitisand pages 1-2) - Autoimmune encephalopathy (often used in broader clinical coding; discussed as “related autoimmune encephalopathy” in clinical practice series) (orozco2023autoimmuneencephalitiscriteria pages 1-3)

1.4 Evidence sources (patient-level vs aggregated)

Evidence in this report is derived from: - Aggregated consensus guidelines (Canadian 2024; Brazilian 2024) (hahn2024canadianconsensusguidelines pages 8-9, dutra2024brazilianconsensusrecommendations pages 5-7) - Retrospective and nationwide observational cohorts (Mayo Clinic clinical practice study; Netherlands nationwide antibody-testing cohort) (orozco2023autoimmuneencephalitiscriteria pages 1-3, kerstens2024autoimmuneencephalitisand pages 1-2) - Diagnostic criteria validation and mimic studies (national referral center cohort) (steenhoven2023mimicsofautoimmune pages 1-2)

2. Etiology

2.1 Disease causal factors (mechanistic categories)

AE is typically conceptualized as antibody-associated immune-mediated encephalitis. Antibodies may target extracellular antigens (often considered directly pathogenic) or intracellular antigens (frequently paraneoplastic syndromes). (steenhoven2023mimicsofautoimmune pages 1-2, kerstens2024autoimmuneencephalitisand pages 1-2)

2.2 Risk factors

2.2.1 Neoplasm / paraneoplastic association

Neoplasm association varies by antibody subtype. Canadian consensus emphasizes that “all subtypes of AIE may be associated with an underlying neoplasm at varying frequencies” and recommends malignancy screening for all initial adult AE presentations. (hahn2024canadianconsensusguidelines pages 9-10)

Canadian guidance provides a malignancy-risk stratification by antibody (Table 4), e.g. high-risk antibodies (>70%) including Hu/ANNA1, Yo/PCA1, Ma2, KLHL11, etc.; intermediate risk (30–70%) including NMDAR, AMPAR, GABABR; and low risk (<30%) including LGI1, GFAP, GAD65, MOG. (hahn2024canadianconsensusguidelines pages 10-11)

2.2.2 Post-infectious triggers

Post-infectious immune mechanisms are recognized clinically (e.g., secondary AE after herpes encephalitis is a known paradigm in AE practice), and both Canadian and Brazilian guidance require early infectious exclusion (notably HSV PCR in CSF) during diagnostic evaluation. (dutra2024brazilianconsensusrecommendations pages 7-8, dutra2024brazilianconsensusrecommendations pages 5-7)

2.2.3 Iatrogenic triggers (immune checkpoint inhibitors)

Immune checkpoint inhibitor (ICI)-related encephalitis is recognized as an AE phenotype and is treated with immunosuppressive strategies; Canadian consensus notes ICI therapy as a risk factor and discusses AE in the differential of acute encephalopathy. (hahn2024canadianconsensusguidelines pages 2-3)

2.2.4 Genetic susceptibility (HLA/KIR)

Genetic predisposition is increasingly studied; however, in this run, detailed HLA/KIR evidence was retrieved but not processed into the evidence set with citable context IDs. Therefore, genetic susceptibility is not exhaustively summarized here.

2.3 Protective factors

Protective genetic or environmental factors were not explicitly reported in the retrieved, citable evidence for this run.

2.4 Gene–environment interactions

While environmental triggers (tumor, infection, ICI exposure) are recognized, explicit gene–environment interaction analyses were not available in the citable evidence retrieved for this run.

3. Phenotypes

3.1 Core clinical phenotype spectrum (with frequencies where available)

A Chinese cohort of neuronal-surface antibody AE (n=103) reported presenting frequencies: seizures 74.8%, psychiatric/behavior disorders 66.0%, cognitive deficits 51.5%, disturbances of consciousness 45.6%, and movement disorders/involuntary movements 26.2%. (huang2023clinicalcharacteristicsand pages 1-2)

In the Mayo Clinic real-world series of 538 adults (AE or related autoimmune encephalopathy), “possible AE” required subacute onset plus supportive features; among supportive features within possible AE (n=361), focal findings, seizures, supportive MRI, and CSF pleocytosis were common (as summarized in the paper’s abstract). (orozco2023autoimmuneencephalitiscriteria pages 1-3)

3.2 Suggested HPO terms (examples for knowledge base)

Based on the phenotype frequencies and guideline descriptions in the cited cohorts: - Seizures — HP:0001250 (huang2023clinicalcharacteristicsand pages 1-2) - Psychiatric symptoms / psychosis — HP:0000708 / HP:0000738 (huang2023clinicalcharacteristicsand pages 1-2) - Cognitive impairment — HP:0100543 (huang2023clinicalcharacteristicsand pages 1-2) - Altered mental status / impaired consciousness — HP:0001252 (huang2023clinicalcharacteristicsand pages 1-2) - Movement disorder / dyskinesia — HP:0100022 (huang2023clinicalcharacteristicsand pages 1-2) - CSF pleocytosis — HP:0002181 (dutra2024brazilianconsensusrecommendations pages 4-5)

3.3 Quality of life impact

Guidelines emphasize persistent neuropsychiatric and cognitive sequelae and the need to evaluate cognitive/functional outcomes using tools beyond mRS (e.g., CASE, MMSE, MoCA). (dutra2024brazilianconsensusrecommendations pages 8-10, hahn2024canadianconsensusguidelines pages 10-11)

4. Genetic/Molecular Information

4.1 Primary molecular targets (autoantibodies)

Netherlands nationwide testing study lists major extracellular antigen (EA) targets including NMDAR, LGI1, CASPR2, GABABR, GABAAR, AMPAR, DPPX, GlyR, mGluR1, IgLON5, Tr/DNER and intracellular antigen (IA) targets including Hu/ANNA1, Yo/PCA1, CRMP5/CV2, Ri/ANNA2, Ma1/Ma2, amphiphysin, GAD65, GFAP, KLHL11. (kerstens2024autoimmuneencephalitisand pages 1-2)

In that nationwide cohort, the four most common AIE/PNS types were anti-NMDAR, anti-LGI1, anti-Hu, and anti-GAD65, comprising 364/578 (63.0%) of diagnoses. (kerstens2024autoimmuneencephalitisand pages 1-2)

4.2 Causal genes and pathogenic variants

AE is generally not a monogenic disease; causal Mendelian genes and variant-level pathogenicity (ClinVar-style) were not provided in the citable evidence retrieved in this run.

4.3 Epigenetic information, chromosomal abnormalities

Not reported in the citable evidence retrieved in this run.

5. Environmental Information

5.1 Infectious agents

Workup guidelines emphasize exclusion of infectious encephalitis, specifically recommending CSF PCR testing for herpesviruses as part of AE evaluation and prior to/alongside immunotherapy. (dutra2024brazilianconsensusrecommendations pages 7-8, dutra2024brazilianconsensusrecommendations pages 5-7)

5.2 Neoplasm-associated immune triggers

Neoplasm association is managed as a core environmental/biologic trigger; all adult AE presentations should undergo malignancy screening at diagnosis. (hahn2024canadianconsensusguidelines pages 9-10)

6. Mechanism / Pathophysiology

6.1 Mechanistic framing (causal chain)

A practical mechanistic chain in antibody-mediated AE is: 1) Triggering exposure (e.g., tumor expression of neural antigens, infection, or immune checkpoint dysregulation) → 2) Immune activation and production of neural-specific antibodies (and/or T-cell responses, particularly in intracellular-antigen/paraneoplastic syndromes) → 3) CNS access with neuroinflammation (variable MRI/CSF abnormalities; sometimes normal early) → 4) Disruption of neuronal networks leading to neuropsychiatric symptoms, seizures, cognitive deficits, movement disorders.

This framing is consistent with the guideline and cohort emphasis that extracellular-antigen AE is directly pathogenic and that MRI/EEG/CSF may be normal despite AE. (steenhoven2023mimicsofautoimmune pages 1-2, hahn2024canadianconsensusguidelines pages 6-7)

6.2 Suggested GO biological process terms (examples)

  • GO:0006954 inflammatory response
  • GO:0006955 immune response
  • GO:0042113 B cell activation
  • GO:0002376 immune system process

6.3 Suggested CL (Cell Ontology) terms (examples)

  • B cell — CL:0000236
  • Plasma cell — CL:0000786
  • T cell — CL:0000084
  • Microglial cell — CL:0000129

6.4 Suggested UBERON anatomy terms (examples)

Given the encephalitic phenotype and limbic predominance in multiple AE syndromes: - Brain — UBERON:0000955 - Hippocampus — UBERON:0001954 - Amygdala — UBERON:0001876

7. Anatomical Structures Affected

7.1 Organ/system level

Primary affected system is the central nervous system (CNS), with presentations including limbic encephalitis phenotypes and diffuse encephalopathy. (orozco2023autoimmuneencephalitiscriteria pages 1-3, hahn2024canadianconsensusguidelines pages 10-11)

7.2 Tissue/cell level

The evidence base in this run does not provide histopathology-level cell targeting across AE subtypes; however, antibody-associated mechanisms imply neuronal synaptic/extracellular target involvement for many EA antibodies and broader neuroinflammatory involvement in some cases. (kerstens2024autoimmuneencephalitisand pages 1-2, steenhoven2023mimicsofautoimmune pages 1-2)

8. Temporal Development

8.1 Onset

Core criteria and guidelines define onset as subacute, typically rapid progression within <3 months for possible AE. (dutra2024brazilianconsensusrecommendations pages 4-5)

8.2 Progression/course patterns

Relapse is a recognized course feature. Canadian consensus defines relapse as objective worsening after improvement or plateau, “usually at least 2–3 months from the original presentation” and preferably supported by MRI/CSF inflammation. (hahn2024canadianconsensusguidelines pages 12-13)

9. Inheritance and Population

9.1 Epidemiology (incidence)

A Netherlands nationwide retrospective cohort (2016–2021) estimated AE/paraneoplastic neurologic syndrome (AIE/PNS) incidence increasing from 4.70 per million person-years (2016) to 5.76 per million person-years (2021), with overall incidence 5.57 per million person-years (95% CI 5.13–6.05). (kerstens2024autoimmuneencephalitisand pages 1-2)

9.2 Demographics

The Canadian consensus notes antibody-specific demographic patterns (e.g., NMDAR tends to affect children/young women; LGI1 often in older men) but does not provide cohort-level sex-ratio statistics in the citable excerpts for this run. (hahn2024canadianconsensusguidelines pages 2-3)

10. Diagnostics

10.1 Clinical criteria and workflow

The Graus 2016 “possible AE” criteria (adult) are a widely implemented entry step: subacute onset plus ≥1 supportive feature and exclusion of alternative causes. (orozco2023autoimmuneencephalitiscriteria pages 1-3, dutra2024brazilianconsensusrecommendations pages 4-5)

A structured diagnostic workflow is supported by both Brazilian and Canadian consensus: - Brain MRI, EEG, CSF analysis including IgG index and oligoclonal bands (OCBs). (dutra2024brazilianconsensusrecommendations pages 5-7) - Infectious exclusion, including CSF PCR for herpesviruses. (dutra2024brazilianconsensusrecommendations pages 7-8, dutra2024brazilianconsensusrecommendations pages 5-7) - Neural antibody testing using paired serum+CSF (Brazil explicitly recommends TBA + CBA). (dutra2024brazilianconsensusrecommendations pages 5-7)

A concise, evidence-backed diagnostic criteria/performance and workflow summary is provided in the table artifact below.

Topic Key points (with numbers) Evidence type Source (authors/year/journal) URL
Graus 2016 possible AE criteria Adult possible AE requires all 3: (1) subacute onset, rapid progression in <3 months, of working memory deficits/altered mental status/psychiatric symptoms; (2) ≥1 supportive feature: new focal CNS findings, unexplained seizures, CSF pleocytosis, or MRI suggestive of encephalitis; (3) reasonable exclusion of alternative causes. In Mayo real-world application, 361/538 (67%) met at least possible criteria. (orozco2023autoimmuneencephalitiscriteria pages 1-3, dutra2024brazilianconsensusrecommendations pages 4-5) Human clinical cohort + consensus criteria Orozco et al. 2023, Neurology Clinical Practice; Dutra et al. 2024, Arquivos de Neuro-Psiquiatria https://doi.org/10.1212/cpj.0000000000200151 ; https://doi.org/10.1055/s-0044-1788586
Pediatric possible AE criteria Pediatric possible AE: onset of neurologic/psychiatric symptoms over <3 months in a previously healthy child plus 2 of the following: altered mental status/EEG slowing or epileptiform activity, focal deficits, cognitive difficulties, acute developmental regression, movement disorder, psychiatric symptoms, or unexplained seizures; and exclusion of alternatives. (dutra2024brazilianconsensusrecommendations pages 4-5) Consensus criteria Dutra et al. 2024, Arquivos de Neuro-Psiquiatria https://doi.org/10.1055/s-0044-1788586
Criteria performance and specificity In a national referral cohort (n=239), criteria performance was: possible AE sensitivity 83%, specificity 27%; definite autoimmune limbic encephalitis sensitivity 10%, specificity 98%; probable anti-NMDAR sensitivity 50%, specificity 96%; probable seronegative AE specificity 99%; proposed probable anti-LGI1 sensitivity 66%, specificity 96%. Authors note probable/definite categories are useful for early immunotherapy decisions because specificity is high. (steenhoven2023mimicsofautoimmune pages 1-2) Human clinical validation cohort van Steenhoven et al. 2023, Neurology Neuroimmunology & Neuroinflammation https://doi.org/10.1212/nxi.0000000000200148
Definite AE / antibody-defined cases in practice In Mayo review (n=538), definite AE cases included limbic encephalitis 127/221 (57%), anti-NMDAR 32/221 (15%), ADEM 8/221 (4%), and other AE-specific IgG defined syndromes 54/221 (24%). Most common definite AE-IgGs: LGI1 76 (34%), NMDA-R 32 (16%), high-titer GAD65 23 (12%). Criteria were judged highly specific but may miss AE-IgG positive isolated seizures/brainstem disease. (orozco2023autoimmuneencephalitiscriteria pages 1-3) Human clinical cohort Orozco et al. 2023, Neurology Clinical Practice https://doi.org/10.1212/cpj.0000000000200151
Common mimics and diagnostic pitfalls Among 239 suspected cases, AE was 104/239 (44%) and mimics 109/239 (46%). Common mimics: neuroinflammatory CNS disorders 26%, psychiatric disorders 19%, noninflammatory epilepsy 13%, CNS infections 7%, neurodegenerative diseases 7%, CNS neoplasms 6%. Confounders included mesiotemporal MRI lesions 17% and false-positive serum antibodies 12%; atypical mesiotemporal features were more frequent in mimics (61% vs 24%). (steenhoven2023mimicsofautoimmune pages 1-2) Human clinical cohort van Steenhoven et al. 2023, Neurology Neuroimmunology & Neuroinflammation https://doi.org/10.1212/nxi.0000000000200148
Antibody assay PPV limitations Nationwide Netherlands testing (30,246 samples) found 2,877 (9.5%) positive samples from 1,228 patients; clinical data on 940 patients yielded 578 AIE/PNS diagnoses. Sensitivity and specificity were generally >95% to >99%, but PPV was only moderate-to-poor in mass testing; for serum intracellular-antigen antibodies PPV ranged 25%–80%. This supports cautious interpretation of positive serum results in low-pretest-probability settings. (kerstens2024autoimmuneencephalitisand pages 1-2) Nationwide retrospective laboratory-clinical cohort Kerstens et al. 2024, Neurology Neuroimmunology & Neuroinflammation https://doi.org/10.1212/nxi.0000000000200318
Core diagnostic workflow tests Brazilian consensus recommends that adults meeting Graus possible AE or children meeting Cellucci criteria should undergo brain MRI, EEG, and CSF analysis, including IgG index and oligoclonal bands (OCBs). These are baseline tests before/alongside antibody evaluation. (dutra2024brazilianconsensusrecommendations pages 5-7, dutra2024brazilianconsensusrecommendations pages 4-5) Consensus guideline Dutra et al. 2024, Arquivos de Neuro-Psiquiatria https://doi.org/10.1055/s-0044-1788586
CSF infectious exclusion and paired antibody testing Consensus recommends paired serum + CSF antineuronal antibody testing using TBA and CBA; anti-MOG should be added in all pediatric possible AE. CSF workup should include PCR for herpesvirus; sample collection should preferably occur before immunotherapy, but treatment should not be delayed while awaiting results. (dutra2024brazilianconsensusrecommendations pages 5-7) Consensus guideline Dutra et al. 2024, Arquivos de Neuro-Psiquiatria https://doi.org/10.1055/s-0044-1788586
Imaging caveats and antibody confirmation Canadian guidance emphasizes MRI/EEG may be normal and unexpected antibody results should prompt confirmatory testing (e.g., tissue indirect immunofluorescence/immunohistochemistry). Initial screening should not wait for antibody results. (hahn2024canadianconsensusguidelines pages 9-10, hahn2024canadianconsensusguidelines pages 10-11) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences https://doi.org/10.1017/cjn.2024.16
Neoplasm screening: who to screen All adult patients with AIE should undergo malignancy screening at diagnosis; screening should not be delayed while awaiting neural antibody results. Screening should also be considered at relapse. (hahn2024canadianconsensusguidelines pages 9-10, hahn2024canadianconsensusguidelines pages 10-11) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences https://doi.org/10.1017/cjn.2024.16
Neoplasm screening: three-step approach Canadian consensus describes a 3-step imaging strategy: (1) conventional CT body, (2) focused sex-specific imaging, and (3) whole-body PET if needed; terminate early if a neoplasm is found. First-line PET can be considered when there is a strong antibody-neoplasm association. Pelvic US or MRI is preferred over PET for ovarian teratoma. (hahn2024canadianconsensusguidelines pages 9-10, hahn2024canadianconsensusguidelines pages 10-11) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences https://doi.org/10.1017/cjn.2024.16
Sex-specific / directed tumor studies Examples of directed testing include immediate ovarian ultrasound for young women with NMDAR encephalitis and testicular ultrasound for men with KLHL11 antibody encephalitis. Brazilian consensus similarly recommends CT chest/abdomen/pelvis plus sex-specific studies such as transvaginal US/mammography for women and scrotal US for men. (hahn2024canadianconsensusguidelines pages 10-11, dutra2024brazilianconsensusrecommendations pages 5-7) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences; Dutra et al. 2024, Arquivos de Neuro-Psiquiatria https://doi.org/10.1017/cjn.2024.16 ; https://doi.org/10.1055/s-0044-1788586
Follow-up tumor surveillance If initial screening is negative, Canadian guidance recommends follow-up screening in patients with intermediate- or high-risk antibodies; for such antibodies, repeat screening every 3–6 months for at least 2 years is recommended. Antibody-negative patients with high-risk phenotypes (e.g., limbic encephalitis, refractory/relapsing disease, malignancy risk factors) may also merit repeat screening. (hahn2024canadianconsensusguidelines pages 9-10, hahn2024canadianconsensusguidelines pages 10-11) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences https://doi.org/10.1017/cjn.2024.16
Malignancy-risk antibody categories Canadian Table 4 classifies tumor risk: high-risk >70% (e.g., Hu/ANNA-1, CV2/CRMP5, Ma2/Ma, KLHL11, Yo/PCA-1), intermediate 30–70% (e.g., AMPAR, GABABR, mGluR5, NMDAR, CASPR2 in Morvan syndrome, GABAAR), and low-risk <30% (e.g., GFAP, GAD65, LGI1, DPPX, GlyR, MOG, AQP4, mGluR1). (hahn2024canadianconsensusguidelines pages 10-11) Consensus guideline Hahn et al. 2024, Canadian Journal of Neurological Sciences https://doi.org/10.1017/cjn.2024.16

Table: This table summarizes evidence-based autoimmune encephalitis diagnostic criteria, common pitfalls, core testing workflow, and neoplasm screening recommendations from recent validation studies and 2024 consensus guidelines. It is useful as a compact reference for applying Graus/Cellucci criteria, interpreting antibody results cautiously, and structuring tumor search in suspected AE.

10.2 Diagnostic criteria performance and misdiagnosis pitfalls

In a real-world validation/mimic cohort (n=239), “possible AE” criteria had sensitivity 83% and specificity 27%, reflecting usefulness as an entry criterion but a high false-positive burden; “definite autoimmune limbic encephalitis” had specificity 98%, and “probable anti-NMDAR” had specificity 96%. (steenhoven2023mimicsofautoimmune pages 1-2)

Key pitfalls include: - False-positive serum antibodies (reported in 12% of the mimic/AE referral cohort). (steenhoven2023mimicsofautoimmune pages 1-2) - In mass-testing settings, PPV can be only modest: in the Netherlands nationwide antibody-testing cohort, serum intracellular-antigen antibody PPVs ranged 25%–80%, despite high sensitivity/specificity for most assays. (kerstens2024autoimmuneencephalitisand pages 1-2)

10.3 Imaging and electrophysiology (recent data)

Canadian consensus states FDG-PET can be more sensitive than MRI in AE (reported 87% vs 25–50% sensitivity) but warns that PET findings can be nonspecific and should not be used alone. (hahn2024canadianconsensusguidelines pages 6-7, hahn2024canadianconsensusguidelines pages 12-13)

10.4 Neoplasm screening (real-world implementation)

Canadian consensus recommends malignancy screening for all adult AE at diagnosis and describes a 3-step imaging strategy (CT body → sex-specific imaging → whole-body PET if needed), with follow-up screening focused on intermediate/high-risk antibodies. (hahn2024canadianconsensusguidelines pages 9-10, hahn2024canadianconsensusguidelines pages 10-11)

The neoplasm screening protocol figure from the Canadian guideline is shown here. (hahn2024canadianconsensusguidelines media d7e73b99)

11. Outcome / Prognosis

11.1 Functional outcomes

In the Chinese cohort (n=103), most patients achieved favorable function at last follow-up: 78 had good prognosis (mRS 0–2) vs 21 with poor prognosis (mRS 3–6); anti-GABABR encephalitis had worse outcomes than other AE subtypes. (huang2023clinicalcharacteristicsand pages 1-2)

11.2 Prognostic factors and biomarkers

In the same cohort, elevated neutrophil-to-lymphocyte ratio (NLR) and tumor presence were independent predictors of poor prognosis; a model combining these achieved AUC 0.847 (95% CI 0.733–0.961). (huang2023clinicalcharacteristicsand pages 1-2)

11.3 Relapse

Canadian consensus summarizes retrospective relapse rates in NMDAR/LGI1/CASPR2 encephalitis as 10–41% and notes relapses may be similar, milder, or with a different core syndrome. (hahn2024canadianconsensusguidelines pages 12-13)

12. Treatment

12.1 Acute immunotherapy tiers (consensus practice)

12.1.1 Timing

Brazilian consensus explicitly states: “Treatment should be started within the first 4 weeks of symptoms,” and that initiation “should not be delayed while waiting for” antibody results. (dutra2024brazilianconsensusrecommendations pages 1-2, dutra2024brazilianconsensusrecommendations pages 5-7)

12.1.2 First-line therapy

Brazilian consensus: first-line is methylprednisolone + IVIG or methylprednisolone + plasmapheresis, with typical IVIG and steroid dosing specified (e.g., IVIG 2 g/kg over 2–5 days; IV methylprednisolone 1,000 mg daily for 3–5 days in adults). (dutra2024brazilianconsensusrecommendations pages 8-10, dutra2024brazilianconsensusrecommendations pages 5-7)

Canadian consensus: severe AE should receive high-dose corticosteroids with IVIG or plasma exchange as initial therapy; mild/moderate cases may consider steroid monotherapy with specialist input. (hahn2024canadianconsensusguidelines pages 9-10)

The Canadian guideline treatment algorithm figure is shown here. (hahn2024canadianconsensusguidelines media aed80ffe)

12.1.3 Second-line therapy and escalation timing

Brazilian consensus defines “satisfactory clinical response” as improvement within 10–14 days; lack of partial improvement within 14 days should prompt second-line therapy. (dutra2024brazilianconsensusrecommendations pages 5-7)

Canadian consensus defines first-line failure as no improvement/worsening at 5–10 days in severe AE and 2–4 weeks in mild/moderate AE. (hahn2024canadianconsensusguidelines pages 8-9)

Second-line choices are antibody-contextual: - Cell-surface antibody AE or antibody-negative AE: rituximab favored for efficacy/safety. (hahn2024canadianconsensusguidelines pages 8-9) - High-risk paraneoplastic/intracellular antibodies: cyclophosphamide preferentially used. (hahn2024canadianconsensusguidelines pages 8-9)

12.1.4 Third-line / refractory options

Canadian and Brazilian guidance list tocilizumab and bortezomib as third-line/experimental options for cases refractory to second-line therapy, with specialist involvement recommended. (hahn2024canadianconsensusguidelines pages 9-10, dutra2024brazilianconsensusrecommendations pages 5-7)

12.2 Symptomatic treatments

Seizures in AE are commonly acute symptomatic; Brazilian consensus notes antiseizure medications may be weaned after the acute stage when stable. (dutra2024brazilianconsensusrecommendations pages 1-2)

12.3 MAXO term suggestions (examples)

  • High-dose corticosteroid therapy — MAXO:0000601 (suggested)
  • Intravenous immunoglobulin therapy — MAXO:0000747 (suggested)
  • Therapeutic plasma exchange — MAXO:0000474 (suggested)
  • Anti-CD20 monoclonal antibody therapy (rituximab) — MAXO:0000792 (suggested)

13. Prevention

Primary prevention is not established for most AE syndromes given heterogeneous triggers. Secondary/tertiary prevention is emphasized via: - Early diagnosis and early immunotherapy to reduce morbidity and long-term deficits. (dutra2024brazilianconsensusrecommendations pages 5-7, hahn2024canadianconsensusguidelines pages 9-10) - Tumor screening and treatment/removal when present (paraneoplastic prevention of ongoing antigenic drive). (hahn2024canadianconsensusguidelines pages 9-10)

14. Other Species / Natural Disease

Naturally occurring AE-like antibody-mediated encephalitis in non-human species was not addressed in the citable evidence retrieved in this run.

15. Model Organisms

Animal/model system evidence was not present in the citable evidence retrieved in this run.

Expert opinion & analysis (from authoritative sources)

  • Diagnostic criteria are useful but require caution: real-world studies highlight that entry criteria (“possible AE”) are sensitive but not specific and are prone to mimics and misdiagnosis; high-specificity categories (probable/definite) support early immunotherapy decisions while awaiting antibody confirmation. (steenhoven2023mimicsofautoimmune pages 1-2)
  • Testing pitfalls are central in modern practice: even when assays show high analytical specificity/sensitivity, PPV can be limited in rare diseases under broad testing, especially for serum intracellular antibodies, reinforcing the need for clinical correlation and confirmatory strategies. (kerstens2024autoimmuneencephalitisand pages 1-2, steenhoven2023mimicsofautoimmune pages 1-2)
  • Treatment is time-sensitive and tiered: 2024 consensus statements converge on early immunotherapy (often combination first-line in severe disease) and time-bound escalation to second-line agents if not improving. (hahn2024canadianconsensusguidelines pages 8-9, dutra2024brazilianconsensusrecommendations pages 5-7)

Key images (evidence)

  • Canadian guideline treatment algorithm: (hahn2024canadianconsensusguidelines media aed80ffe)
  • Canadian guideline neoplasm screening protocol: (hahn2024canadianconsensusguidelines media d7e73b99)

Notes on evidence gaps in this run

  • Standard ontology identifiers (MONDO/Orphanet/MeSH/ICD) were not retrievable from the cited evidence corpus.
  • Protective factors, epigenetic mechanisms, and non-human models were not available in the retrieved citable sources.

References

  1. (steenhoven2023mimicsofautoimmune pages 1-2): Robin W. Van Steenhoven, Juna M. de Vries, Arlette L. Bruijstens, Manuela Paunovic, Mariska M. Nagtzaam, Suzanne C. Franken, Anna E. Bastiaansen, Marienke A. De Bruijn, Agnes Van Sonderen, Marco W.J. Schreurs, Mayke Gardeniers, Robert M. Verdijk, Rutger K. Balvers, Peter A. Sillevis Smitt, Rinze F. Neuteboom, and Maarten J. Titulaer. Mimics of autoimmune encephalitis. Neurology Neuroimmunology & Neuroinflammation, Nov 2023. URL: https://doi.org/10.1212/nxi.0000000000200148, doi:10.1212/nxi.0000000000200148. This article has 72 citations.

  2. (orozco2023autoimmuneencephalitiscriteria pages 1-3): Emma Orozco, Cristina Valencia-Sanchez, Jeffrey Britton, Divyanshu Dubey, Eoin P. Flanagan, A. Sebastian Lopez-Chiriboga, Nicholas Zalewski, Anastasia Zekeridou, Sean J. Pittock, and Andrew McKeon. Autoimmune encephalitis criteria in clinical practice. Neurology Clinical Practice, Jun 2023. URL: https://doi.org/10.1212/cpj.0000000000200151, doi:10.1212/cpj.0000000000200151. This article has 65 citations.

  3. (dutra2024brazilianconsensusrecommendations pages 4-5): Lívia Almeida Dutra, Pedro Victor de Castro Silva, João Henrique Fregadolli Ferreira, Alexandre Coelho Marques, Fabio Fieni Toso, Claudia Cristina Ferreira Vasconcelos, Doralina Guimarães Brum, Samira Luisa dos Apóstolos Pereira, Tarso Adoni, Leticia Januzi de Almeida Rocha, Leticia Pereira de Brito Sampaio, Nise Alessandra de Carvalho Sousa, Renata Barbosa Paolilo, Angélica Dal Pizzol, Bruna Klein da Costa, Caio César Diniz Disserol, Camila Pupe, Daniel Almeida do Valle, Denise Sisterolli Diniz, Fabiano Ferreira de Abrantes, Felipe da Rocha Schmidt, Fernando Cendes, Francisco Tomaz Meneses de Oliveira, Gabriela Joca Martins, Guilherme Diogo Silva, Katia Lin, Lécio Figueira Pinto, Mara Lúcia Schimtz Ferreira Santos, Marcus Vinícius Magno Gonçalves, Mariana Braatz Krueger, Michel Elyas Jung Haziot, Orlando Graziani Povoas Barsottini, Osvaldo José Moreira do Nascimento, Paulo Ribeiro Nóbrega, Priscilla Mara Proveti, Raphael Machado do Castilhos, Vanessa Daccach, and Felipe von Glehn. Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations. Arquivos de Neuro-Psiquiatria, 82:001-015, Jul 2024. URL: https://doi.org/10.1055/s-0044-1788586, doi:10.1055/s-0044-1788586. This article has 10 citations and is from a peer-reviewed journal.

  4. (dutra2024brazilianconsensusrecommendations pages 1-2): Lívia Almeida Dutra, Pedro Victor de Castro Silva, João Henrique Fregadolli Ferreira, Alexandre Coelho Marques, Fabio Fieni Toso, Claudia Cristina Ferreira Vasconcelos, Doralina Guimarães Brum, Samira Luisa dos Apóstolos Pereira, Tarso Adoni, Leticia Januzi de Almeida Rocha, Leticia Pereira de Brito Sampaio, Nise Alessandra de Carvalho Sousa, Renata Barbosa Paolilo, Angélica Dal Pizzol, Bruna Klein da Costa, Caio César Diniz Disserol, Camila Pupe, Daniel Almeida do Valle, Denise Sisterolli Diniz, Fabiano Ferreira de Abrantes, Felipe da Rocha Schmidt, Fernando Cendes, Francisco Tomaz Meneses de Oliveira, Gabriela Joca Martins, Guilherme Diogo Silva, Katia Lin, Lécio Figueira Pinto, Mara Lúcia Schimtz Ferreira Santos, Marcus Vinícius Magno Gonçalves, Mariana Braatz Krueger, Michel Elyas Jung Haziot, Orlando Graziani Povoas Barsottini, Osvaldo José Moreira do Nascimento, Paulo Ribeiro Nóbrega, Priscilla Mara Proveti, Raphael Machado do Castilhos, Vanessa Daccach, and Felipe von Glehn. Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations. Arquivos de Neuro-Psiquiatria, 82:001-015, Jul 2024. URL: https://doi.org/10.1055/s-0044-1788586, doi:10.1055/s-0044-1788586. This article has 10 citations and is from a peer-reviewed journal.

  5. (kerstens2024autoimmuneencephalitisand pages 1-2): Jeroen Kerstens, Marco W.J. Schreurs, Juna M. de Vries, Rinze F. Neuteboom, Juliette Brenner, Yvette S. Crijnen, Robin W. van Steenhoven, Marienke A.A.M. de Bruijn, Agnes van Sonderen, Marleen H. van Coevorden-Hameete, Anna E.M. Bastiaansen, Marie R. Vermeiren, Jan G.M.C. Damoiseaux, Henny G. Otten, Catharina J.M. Frijns, Bob Meek, Anouk C.M. Platteel, Alina van de Mortel, Cathérine C.S. Delnooz, Maarten A.C. Broeren, Marcel M. Verbeek, Erik I. Hoff, Sanae Boukhrissi, Suzanne C. Franken, Mariska M.P. Nagtzaam, Manuela Paunovic, Sharon Veenbergen, Peter A.E. Sillevis Smitt, and Maarten J. Titulaer. Autoimmune encephalitis and paraneoplastic neurologic syndromes. Neurology Neuroimmunology & Neuroinflammation, Nov 2024. URL: https://doi.org/10.1212/nxi.0000000000200318, doi:10.1212/nxi.0000000000200318. This article has 29 citations.

  6. (hahn2024canadianconsensusguidelines pages 8-9): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  7. (dutra2024brazilianconsensusrecommendations pages 5-7): Lívia Almeida Dutra, Pedro Victor de Castro Silva, João Henrique Fregadolli Ferreira, Alexandre Coelho Marques, Fabio Fieni Toso, Claudia Cristina Ferreira Vasconcelos, Doralina Guimarães Brum, Samira Luisa dos Apóstolos Pereira, Tarso Adoni, Leticia Januzi de Almeida Rocha, Leticia Pereira de Brito Sampaio, Nise Alessandra de Carvalho Sousa, Renata Barbosa Paolilo, Angélica Dal Pizzol, Bruna Klein da Costa, Caio César Diniz Disserol, Camila Pupe, Daniel Almeida do Valle, Denise Sisterolli Diniz, Fabiano Ferreira de Abrantes, Felipe da Rocha Schmidt, Fernando Cendes, Francisco Tomaz Meneses de Oliveira, Gabriela Joca Martins, Guilherme Diogo Silva, Katia Lin, Lécio Figueira Pinto, Mara Lúcia Schimtz Ferreira Santos, Marcus Vinícius Magno Gonçalves, Mariana Braatz Krueger, Michel Elyas Jung Haziot, Orlando Graziani Povoas Barsottini, Osvaldo José Moreira do Nascimento, Paulo Ribeiro Nóbrega, Priscilla Mara Proveti, Raphael Machado do Castilhos, Vanessa Daccach, and Felipe von Glehn. Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations. Arquivos de Neuro-Psiquiatria, 82:001-015, Jul 2024. URL: https://doi.org/10.1055/s-0044-1788586, doi:10.1055/s-0044-1788586. This article has 10 citations and is from a peer-reviewed journal.

  8. (hahn2024canadianconsensusguidelines pages 9-10): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  9. (hahn2024canadianconsensusguidelines pages 10-11): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  10. (dutra2024brazilianconsensusrecommendations pages 7-8): Lívia Almeida Dutra, Pedro Victor de Castro Silva, João Henrique Fregadolli Ferreira, Alexandre Coelho Marques, Fabio Fieni Toso, Claudia Cristina Ferreira Vasconcelos, Doralina Guimarães Brum, Samira Luisa dos Apóstolos Pereira, Tarso Adoni, Leticia Januzi de Almeida Rocha, Leticia Pereira de Brito Sampaio, Nise Alessandra de Carvalho Sousa, Renata Barbosa Paolilo, Angélica Dal Pizzol, Bruna Klein da Costa, Caio César Diniz Disserol, Camila Pupe, Daniel Almeida do Valle, Denise Sisterolli Diniz, Fabiano Ferreira de Abrantes, Felipe da Rocha Schmidt, Fernando Cendes, Francisco Tomaz Meneses de Oliveira, Gabriela Joca Martins, Guilherme Diogo Silva, Katia Lin, Lécio Figueira Pinto, Mara Lúcia Schimtz Ferreira Santos, Marcus Vinícius Magno Gonçalves, Mariana Braatz Krueger, Michel Elyas Jung Haziot, Orlando Graziani Povoas Barsottini, Osvaldo José Moreira do Nascimento, Paulo Ribeiro Nóbrega, Priscilla Mara Proveti, Raphael Machado do Castilhos, Vanessa Daccach, and Felipe von Glehn. Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations. Arquivos de Neuro-Psiquiatria, 82:001-015, Jul 2024. URL: https://doi.org/10.1055/s-0044-1788586, doi:10.1055/s-0044-1788586. This article has 10 citations and is from a peer-reviewed journal.

  11. (hahn2024canadianconsensusguidelines pages 2-3): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  12. (huang2023clinicalcharacteristicsand pages 1-2): Teng Huang, Fei Liu, Baojie Wang, Chunjuan Wang, Maolin Hao, and Shougang Guo. Clinical characteristics and prognosis in patients with neuronal surface antibody-mediated autoimmune encephalitis: a single-center cohort study in china. Frontiers in Immunology, Dec 2023. URL: https://doi.org/10.3389/fimmu.2023.1213532, doi:10.3389/fimmu.2023.1213532. This article has 17 citations and is from a peer-reviewed journal.

  13. (dutra2024brazilianconsensusrecommendations pages 8-10): Lívia Almeida Dutra, Pedro Victor de Castro Silva, João Henrique Fregadolli Ferreira, Alexandre Coelho Marques, Fabio Fieni Toso, Claudia Cristina Ferreira Vasconcelos, Doralina Guimarães Brum, Samira Luisa dos Apóstolos Pereira, Tarso Adoni, Leticia Januzi de Almeida Rocha, Leticia Pereira de Brito Sampaio, Nise Alessandra de Carvalho Sousa, Renata Barbosa Paolilo, Angélica Dal Pizzol, Bruna Klein da Costa, Caio César Diniz Disserol, Camila Pupe, Daniel Almeida do Valle, Denise Sisterolli Diniz, Fabiano Ferreira de Abrantes, Felipe da Rocha Schmidt, Fernando Cendes, Francisco Tomaz Meneses de Oliveira, Gabriela Joca Martins, Guilherme Diogo Silva, Katia Lin, Lécio Figueira Pinto, Mara Lúcia Schimtz Ferreira Santos, Marcus Vinícius Magno Gonçalves, Mariana Braatz Krueger, Michel Elyas Jung Haziot, Orlando Graziani Povoas Barsottini, Osvaldo José Moreira do Nascimento, Paulo Ribeiro Nóbrega, Priscilla Mara Proveti, Raphael Machado do Castilhos, Vanessa Daccach, and Felipe von Glehn. Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations. Arquivos de Neuro-Psiquiatria, 82:001-015, Jul 2024. URL: https://doi.org/10.1055/s-0044-1788586, doi:10.1055/s-0044-1788586. This article has 10 citations and is from a peer-reviewed journal.

  14. (hahn2024canadianconsensusguidelines pages 6-7): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  15. (hahn2024canadianconsensusguidelines pages 12-13): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  16. (hahn2024canadianconsensusguidelines media d7e73b99): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.

  17. (hahn2024canadianconsensusguidelines media aed80ffe): Christopher Hahn, Adrian Budhram, Katayoun Alikhani, Nasser AlOhaly, Grayson Beecher, Gregg Blevins, John Brooks, Robert Carruthers, Jacynthe Comtois, Juthaporn Cowan, Paula de Robles, Julien Hébert, Ronak K. Kapadia, Sarah Lapointe, Aaron Mackie, Warren Mason, Brienne McLane, Alexandra Muccilli, Ilia Poliakov, Penelope Smyth, Kimberly G. Williams, Christopher Uy, and Jennifer A. McCombe. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 51:734-754, Feb 2024. URL: https://doi.org/10.1017/cjn.2024.16, doi:10.1017/cjn.2024.16. This article has 33 citations.