Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy that strikes previously healthy school-aged children a few days to two weeks after a nonspecific febrile illness. It is defined as the subgroup of new-onset refractory status epilepticus (NORSE) that requires a preceding febrile infection, and it develops without an identified acute structural, toxic, metabolic, or infectious (CNS pathogen) cause. The leading mechanistic model is a disorder of innate immunity: a febrile trigger drives microglial/inflammasome activation and a pro-convulsant cytokine surge (interleukin-1-beta, interleukin-6), which - together with blood-brain barrier dysfunction - lowers seizure threshold and produces explosive, multifocal, drug-resistant status epilepticus. The illness is biphasic: an acute super-refractory status epilepticus phase (often requiring prolonged anesthetic burst-suppression) is followed, in survivors, by a chronic phase of drug-resistant epilepsy with cognitive and behavioral sequelae. Because the acute and chronic phases are mechanistically distinct endpoints of the same cascade, this entry keeps them as separate downstream nodes rather than bundling them.
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Conditions with similar clinical presentations that must be differentiated from Febrile Infection-Related Epilepsy Syndrome:
name: Febrile Infection-Related Epilepsy Syndrome
creation_date: "2026-07-24T00:00:00Z"
category: Complex
description: >-
Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic
epileptic encephalopathy that strikes previously healthy school-aged children
a few days to two weeks after a nonspecific febrile illness. It is defined as
the subgroup of new-onset refractory status epilepticus (NORSE) that requires a
preceding febrile infection, and it develops without an identified acute
structural, toxic, metabolic, or infectious (CNS pathogen) cause. The leading
mechanistic model is a disorder of innate immunity: a febrile trigger drives
microglial/inflammasome activation and a pro-convulsant cytokine surge
(interleukin-1-beta, interleukin-6), which - together with blood-brain barrier
dysfunction - lowers seizure threshold and produces explosive, multifocal,
drug-resistant status epilepticus. The illness is biphasic: an acute
super-refractory status epilepticus phase (often requiring prolonged anesthetic
burst-suppression) is followed, in survivors, by a chronic phase of
drug-resistant epilepsy with cognitive and behavioral sequelae. Because the
acute and chronic phases are mechanistically distinct endpoints of the same
cascade, this entry keeps them as separate downstream nodes rather than
bundling them.
parents:
- Epilepsy
- Neurological Disease
synonyms:
- FIRES
- AERRPS
- acute encephalitis with refractory repetitive partial seizures
- DESC syndrome
- devastating epileptic encephalopathy in school-aged children
disease_term:
preferred_term: febrile infection-related epilepsy syndrome
term:
id: MONDO:0015584
label: febrile infection-related epilepsy syndrome
mappings:
mondo_mappings:
- term:
id: MONDO:0015584
label: febrile infection-related epilepsy syndrome
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0015584 is the febrile infection-related epilepsy syndrome concept,
the febrile subgroup of NORSE.
prevalence:
- population: Children/adolescents (Germany)
measure_type: ANNUAL_INCIDENCE
prevalence_class: BAND_1_9_PER_1000000
rate_per_100000: 0.1
notes: >-
Orphanet cites an annual incidence on the order of 1 per 1,000,000 in
children/adolescents. FIRES is very rare - only on the order of 100+
well-characterized cases have been published worldwide - and ascertainment is
difficult because the syndrome is defined clinically and by exclusion. It
predominantly affects previously healthy school-aged children.
- population: Children/adolescents (Germany)
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 1.0
notes: >-
Orphanet cites a point prevalence on the order of 1 per 100,000 in
children/adolescents (kept as a separate record from annual incidence, which
is roughly tenfold lower, to avoid conflating the two measures).
diagnosis:
- name: Clinical Diagnosis by Consensus Criteria (Diagnosis of Exclusion)
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
description: >-
FIRES is a clinical diagnosis made when a previously healthy person develops
new-onset refractory status epilepticus after a preceding febrile infection
(typically 24 hours to 2 weeks before onset), once acute structural, toxic,
metabolic, and identifiable infectious/autoimmune causes have been excluded.
Workup includes MRI, EEG, CSF analysis, autoimmune/paraneoplastic antibody
panels, and infectious and metabolic studies - all of which are, by
definition, non-diagnostic of an alternative cause.
results: >-
New-onset refractory status epilepticus with a documented preceding febrile
illness and no identified alternative cause.
evidence:
- reference: PMID:29399791
supports: SUPPORT
evidence_source: OTHER
snippet: "FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus"
explanation: >-
The international consensus definition specifies the diagnostic criteria
for FIRES: a NORSE presentation with a mandatory preceding febrile infection
in the defined time window.
pathophysiology:
- name: Preceding Febrile Infection Trigger
description: >-
A nonspecific febrile illness (usually an upper-respiratory or
gastrointestinal infection) precedes seizure onset by roughly 24 hours to two
weeks in a previously healthy individual. No specific pathogen is consistently
identified in the CNS, and the fever is understood as a trigger of a
maladaptive immune response rather than a direct CNS infection. This node
captures the single concept of the initiating febrile trigger.
role: trigger
cell_types:
- preferred_term: Leukocyte
term:
id: CL:0000738
label: leukocyte
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A preceding febrile infection had been reported in 96% of them"
explanation: >-
In the multicenter cohort, a preceding febrile infection was reported in
96% of FIRES patients - the defining trigger.
downstream:
- target: Innate Neuroinflammatory Activation
causal_link_type: DIRECT
description: >-
The febrile trigger initiates a maladaptive innate immune response in the
CNS.
- name: Functional IL-1RA Deficiency (Permissive Host Factor)
description: >-
A functional deficiency of endogenous interleukin-1 receptor antagonist
(IL-1RA, encoded by IL1RN) is a candidate permissive host factor: with the
natural brake on IL-1-beta signaling weakened, a common febrile trigger can
drive unchecked IL-1-beta activity. This node captures the single concept of
the "loss of the anti-inflammatory brakes" - the gene-environment convergence
at the heart of the leading FIRES model - kept separate from the febrile
trigger and from the downstream inflammatory activation it permits.
role: modifier
cell_types:
- preferred_term: Leukocyte
term:
id: CL:0000738
label: leukocyte
downstream:
- target: Innate Neuroinflammatory Activation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Deficient IL-1RA braking permits unchecked IL-1-beta-driven neuroinflammatory
activation on exposure to the febrile trigger.
evidence:
- reference: PMID:30779222
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity"
explanation: >-
Functionally deficient endogenous IL-1RA activity in FIRES patient cells is
the permissive "loss of brakes" host factor.
- name: Innate Neuroinflammatory Activation
description: >-
The trigger drives activation of brain-resident innate immunity - microglia
and astrocytes - with inflammasome activation and production of
pro-inflammatory cytokines, prominently interleukin-1-beta and interleukin-6.
A genetic predisposition of the innate immune response (e.g., variation in
the IL-1 pathway) is hypothesized. This node captures the single concept of
the central neuroinflammatory driver.
role: mediator
cell_types:
- preferred_term: Microglial cell
term:
id: CL:0000129
label: microglial cell
- preferred_term: Astrocyte
term:
id: CL:0000127
label: astrocyte
biological_processes:
- preferred_term: Microglial cell activation
term:
id: GO:0001774
label: microglial cell activation
modifier: INCREASED
- preferred_term: Interleukin-1 beta production
term:
id: GO:0032611
label: interleukin-1 beta production
modifier: INCREASED
- preferred_term: Interleukin-6 production
term:
id: GO:0032635
label: interleukin-6 production
modifier: INCREASED
evidence:
- reference: PMID:27770579
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES"
explanation: >-
Elevated CSF proinflammatory cytokines that normalized on IL-1 blockade
support a pathogenic neuroinflammatory driver in FIRES.
- reference: PMID:36871188
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "to investigate inflammation using cerebrospinal fluid (CSF) and serum cytokines/chemokines in patients with new-onset refractory status epilepticus (NORSE) to better understand the pathophysiology of NORSE"
explanation: >-
A dedicated cytokine study of NORSE/FIRES supports inflammation as central
to the pathophysiology.
downstream:
- target: Cytokine-Driven Lowering of Seizure Threshold
causal_link_type: DIRECT
description: >-
The cytokine surge acts on neurons to lower seizure threshold.
- target: Blood-Brain Barrier Dysfunction
causal_link_type: DIRECT
description: >-
Neuroinflammation disrupts the blood-brain barrier.
- name: Cytokine-Driven Lowering of Seizure Threshold
description: >-
Interleukin-1-beta and interleukin-6 act on neurons to lower seizure
threshold - enhancing NMDA-receptor-mediated excitation, impairing GABAergic
inhibition, and disrupting glutamate homeostasis. This node captures the
single concept of the cytokine-to-excitability link and conforms to the
shared epilepsy final common pathway.
role: mediator
conforms_to: "epilepsy_excitation_inhibition_imbalance#Ion Channel and Synaptic Dysfunction"
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: INCREASED
downstream:
- target: Cortical Excitation-Inhibition Imbalance
causal_link_type: DIRECT
description: >-
Cytokine-driven changes shift the excitation-inhibition balance toward
hyperexcitability.
- name: Blood-Brain Barrier Dysfunction
description: >-
Neuroinflammation disrupts the blood-brain barrier, which amplifies central
inflammation, permits peripheral immune access, and further destabilizes
neuronal excitability. This node captures the single concept of the
barrier-dysfunction amplifier arm.
role: mediator
cell_types:
- preferred_term: Astrocyte
term:
id: CL:0000127
label: astrocyte
biological_processes:
- preferred_term: Acute inflammatory response
term:
id: GO:0002526
label: acute inflammatory response
modifier: INCREASED
downstream:
- target: Cortical Excitation-Inhibition Imbalance
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Barrier breakdown amplifies the shift toward network hyperexcitability.
- name: Cortical Excitation-Inhibition Imbalance
description: >-
The convergent effect of cytokine action and barrier dysfunction is a shift
of cortical networks toward excitation and hypersynchrony. This node captures
the single concept of the network imbalance and conforms to the shared
epilepsy final common pathway.
role: central_effector
conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
downstream:
- target: Super-Refractory Status Epilepticus
causal_link_type: DIRECT
description: >-
Network hyperexcitability manifests as explosive, drug-resistant status
epilepticus.
- name: Super-Refractory Status Epilepticus
description: >-
The acute phase is explosive-onset, multifocal and bilateral tonic-clonic
status epilepticus that is refractory to standard antiseizure medications and
frequently to anesthetic burst-suppression (super-refractory status
epilepticus), often lasting weeks. This node captures the single concept of
the acute catastrophic endpoint and conforms to the shared epilepsy final
common pathway.
role: consequence
conforms_to: "epilepsy_excitation_inhibition_imbalance#Seizure Generation and Epileptogenesis"
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 77 enrolled patients presented with prolonged refractory status epilepticus"
explanation: >-
FIRES presents acutely as prolonged refractory status epilepticus.
downstream:
- target: Neuronal Injury and Network Reorganization
causal_link_type: DIRECT
description: >-
Prolonged status epilepticus and inflammation injure neurons and reorganize
networks.
- name: Neuronal Injury and Network Reorganization
description: >-
Prolonged status epilepticus and sustained neuroinflammation cause
excitotoxic and inflammatory neuronal injury with mesial-temporal/hippocampal
involvement and progressive atrophy, establishing an epileptogenic network.
This node captures the single concept of the injury/reorganization step that
bridges the acute and chronic phases.
role: mediator
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
downstream:
- target: Chronic Drug-Resistant Epilepsy and Neurocognitive Sequelae
causal_link_type: DIRECT
description: >-
The reorganized, injured network produces chronic epilepsy and cognitive
impairment.
- name: Chronic Drug-Resistant Epilepsy and Neurocognitive Sequelae
description: >-
In survivors, the syndrome transitions to a chronic phase of drug-resistant
(usually focal/multifocal) epilepsy accompanied by cognitive impairment and
behavioral difficulties. This node captures the single concept of the chronic
endpoint, kept distinct from the acute status-epilepticus endpoint, and
conforms to the shared epilepsy final common pathway.
role: consequence
conforms_to: "epilepsy_excitation_inhibition_imbalance#Recurrent Unprovoked Seizures"
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sixty-three patients (93%) had refractory epilepsy at follow-up"
explanation: >-
In survivors, FIRES evolves into chronic refractory epilepsy (93% at
follow-up in the cohort).
- reference: PMID:20813015
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this condition may evolve into pharmacoresistant epilepsy associated with severe cognitive impairment"
explanation: >-
FIRES evolves into pharmacoresistant epilepsy with severe cognitive
impairment - the chronic-phase endpoint.
phenotypes:
- category: Neurologic
name: Refractory Status Epilepticus
description: >-
The defining acute feature is new-onset refractory status epilepticus, often
super-refractory, with explosive multifocal and bilateral tonic-clonic
seizures.
phenotype_term:
preferred_term: Status epilepticus
term:
id: HP:0002133
label: Status epilepticus
temporality: ACUTE
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 77 enrolled patients presented with prolonged refractory status epilepticus"
explanation: >-
FIRES presents with prolonged refractory status epilepticus.
- category: Neurologic
name: Focal Seizures
description: >-
Seizures are typically multifocal, with focal-onset seizures that may become
bilateral tonic-clonic.
phenotype_term:
preferred_term: Focal-onset seizure
term:
id: HP:0007359
label: Focal-onset seizure
- category: Neurologic
name: Bilateral Tonic-Clonic Seizures
description: >-
Focal seizures frequently evolve to bilateral tonic-clonic seizures during
the acute phase.
phenotype_term:
preferred_term: Bilateral tonic-clonic seizure
term:
id: HP:0002069
label: Bilateral tonic-clonic seizure
- category: Constitutional
name: Preceding Fever
description: >-
A nonspecific febrile illness precedes seizure onset by roughly 24 hours to
two weeks and is a mandatory diagnostic feature.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A preceding febrile infection had been reported in 96% of them"
explanation: >-
A preceding febrile infection was reported in 96% of the FIRES cohort.
- category: Neurologic
name: Encephalopathy
description: >-
Encephalopathy accompanies the acute status epilepticus.
phenotype_term:
preferred_term: Encephalopathy
term:
id: HP:0001298
label: Encephalopathy
- category: Neurodevelopmental
name: Cognitive Impairment
description: >-
Survivors are commonly left with cognitive impairment in the chronic phase.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Only 12 of the 68 surviving patients (18%) retained normal cognitive level"
explanation: >-
The great majority of FIRES survivors have cognitive impairment (only 18%
retained a normal cognitive level).
- category: Neurodevelopmental
name: Intellectual Disability
description: >-
Most survivors are left with intellectual disability, frequently severe; only
a small minority retain a normal cognitive level.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Only 12 of the 68 surviving patients (18%) retained normal cognitive level"
explanation: >-
Only 18% of survivors retained a normal cognitive level, indicating
intellectual disability in the great majority.
- category: Neurodevelopmental
name: Behavioral Abnormality
description: >-
Behavioral difficulties are a common part of the chronic neurodevelopmental
sequelae in survivors.
phenotype_term:
preferred_term: Atypical behavior
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:27770579
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "behavior and memory difficulties later in childhood"
explanation: >-
Survivors develop behavior and memory difficulties later in childhood.
- category: Neurologic
name: Chronic Drug-Resistant Epilepsy
description: >-
Survivors develop chronic drug-resistant epilepsy after the acute phase.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
temporality: CHRONIC
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sixty-three patients (93%) had refractory epilepsy at follow-up"
explanation: >-
Survivors are left with chronic refractory epilepsy (93% at follow-up).
biochemical:
- name: Elevated CSF and Serum Pro-Inflammatory Cytokines
presence: INCREASED
context: >-
Elevated cerebrospinal fluid and serum pro-inflammatory cytokines - notably
interleukin-1-beta, interleukin-6, and the interleukin-1 receptor antagonist
(IL-1RA) - are the biochemical signature of innate-immune activation in FIRES
and are being explored as a biomarker to guide immunotherapy.
readouts:
- target: Innate Neuroinflammatory Activation
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Elevated CSF/serum cytokines report the active neuroinflammatory driver of
FIRES.
evidence:
- reference: PMID:30779222
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES"
explanation: >-
Endogenous IL-1RA and IL-1-beta are elevated in the serum and CSF of FIRES
patients - the biochemical cytokine signature.
- reference: PMID:36871188
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "to investigate inflammation using cerebrospinal fluid (CSF) and serum cytokines/chemokines in patients with new-onset refractory status epilepticus (NORSE) to better understand the pathophysiology of NORSE"
explanation: >-
A dedicated CSF/serum cytokine study supports the cytokine/chemokine
signature in NORSE/FIRES.
genetic:
- name: IL1RN
gene_term:
preferred_term: IL1RN
term:
id: hgnc:6000
label: IL1RN
relationship_type: SUSCEPTIBILITY
variant_origin: GERMLINE
notes: >-
IL1RN encodes the endogenous interleukin-1 receptor antagonist (IL-1RA), the
natural brake on IL-1-beta signaling. FIRES is not Mendelian; this is a
candidate host-susceptibility factor rather than an established cause. In a
small study, an index FIRES patient carried IL1RN variants of uncertain
significance with reduced expression of intracellular IL-1RA isoforms, and
functionally attenuated endogenous IL-1RA activity was demonstrated in a few
patients - suggesting a permissive "loss of the anti-inflammatory brakes"
mechanism that may be present in only some children and that also rationalizes
anakinra (recombinant IL-1RA) therapy.
evidence:
- reference: PMID:30779222
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity"
explanation: >-
FIRES patients show reduced intracellular IL-1RA expression and functionally
deficient IL-1RA activity, implicating IL1RN in susceptibility.
- reference: PMID:30779222
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES"
explanation: >-
Endogenous IL-1RA and IL-1-beta are elevated in FIRES serum and CSF,
consistent with active IL-1 pathway inflammation that outstrips the IL-1RA
brake.
datasets: []
differential_diagnoses:
- name: New-Onset Refractory Status Epilepticus (without preceding fever)
description: >-
NORSE is the parent category; FIRES is specifically the subgroup with a
mandatory preceding febrile infection. NORSE cases without a preceding fever,
or with an identified cause, are distinguished on that basis - so FIRES is a
clinical subset defined by the febrile prodrome and by exclusion of other
NORSE etiologies.
disease_term:
preferred_term: new-onset refractory status epilepticus
term:
id: MONDO:0018199
label: new-onset refractory status epilepticus
evidence:
- reference: PMID:29399791
supports: SUPPORT
evidence_source: OTHER
snippet: "NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause"
explanation: >-
The consensus defines NORSE as the parent presentation; FIRES is its
febrile subcategory, which is the basis for distinguishing them.
- name: Anti-NMDA Receptor Encephalitis
description: >-
Anti-NMDA receptor encephalitis is a leading autoimmune mimic that can cause
new-onset refractory status epilepticus; it is distinguished by detection of
anti-NMDAR antibodies and its characteristic psychiatric/dyskinetic
prodrome, and must be excluded before diagnosing FIRES.
disease_term:
preferred_term: anti-NMDA receptor encephalitis
term:
id: MONDO:0021081
label: anti-NMDA receptor encephalitis
- name: Herpes Simplex Encephalitis
description: >-
Herpes simplex (and other viral) encephalitis is a treatable infectious
cause of febrile encephalopathy with seizures that must be excluded (CSF PCR,
MRI) before FIRES is diagnosed, since FIRES requires the absence of an
identified CNS pathogen.
disease_term:
preferred_term: herpes simplex encephalitis
term:
id: MONDO:0012521
label: herpes simplex encephalitis
- name: Dravet Syndrome
description: >-
Dravet syndrome (SCN1A) features fever-sensitive, often prolonged seizures
and status epilepticus and can enter the differential of a febrile-triggered
encephalopathy; it is distinguished by earlier (infantile) onset, the
characteristic evolution, and SCN1A genetic testing.
disease_term:
preferred_term: Dravet syndrome
term:
id: MONDO:0100135
label: Dravet syndrome
treatments:
- name: Anakinra (IL-1 Receptor Antagonist)
description: >-
Anakinra, a recombinant interleukin-1 receptor antagonist, targets the
IL-1-beta-driven neuroinflammation thought to underlie FIRES and is used as an
early targeted immunotherapy, with reports of seizure improvement especially
when started early.
therapeutic_modality: PROTEIN_REPLACEMENT
target_mechanisms:
- target: Innate Neuroinflammatory Activation
treatment_effect: INHIBITS
description: >-
Anakinra blocks IL-1 receptor signaling, dampening the IL-1-beta-driven
neuroinflammatory cascade.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: anakinra
term:
id: CHEBI:231683
label: Anakinra
evidence:
- reference: PMID:27770579
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Anakinra was well tolerated and effective"
explanation: >-
The first report of anakinra in FIRES found it well tolerated and
effective for super-refractory status epilepticus.
- reference: PMID:27770579
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders"
explanation: >-
Anakinra's mechanism is IL-1 receptor antagonism, matching the
IL-1-beta-driven neuroinflammation model of FIRES.
- name: Tocilizumab (IL-6 Receptor Antagonist)
description: >-
Tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, targets the
IL-6-driven arm of the neuroinflammation and is used as a second-line
immunomodulatory option in refractory NORSE/FIRES when IL-1 blockade is
insufficient.
therapeutic_modality: MONOCLONAL_ANTIBODY
target_mechanisms:
- target: Innate Neuroinflammatory Activation
treatment_effect: INHIBITS
description: >-
Tocilizumab blocks IL-6 receptor signaling, reducing the IL-6-driven
inflammatory arm.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Ketogenic Diet
description: >-
The ketogenic diet is a mainstay of FIRES management and can help terminate
refractory status epilepticus, with anti-seizure and anti-inflammatory
effects; early initiation is often recommended.
therapeutic_modality: BEHAVIORAL
target_mechanisms:
- target: Super-Refractory Status Epilepticus
treatment_effect: INHIBITS
description: >-
The ketogenic diet can help terminate refractory status epilepticus.
treatment_term:
preferred_term: ketogenic diet intake
term:
id: NCIT:C173168
label: Ketogenic Diet
evidence:
- reference: PMID:20813015
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In seven patients, KD was efficacious within 2-4 days (mean 2 days) following the onset of ketonuria"
explanation: >-
The ketogenic diet terminated refractory status epilepticus in most FIRES
patients, shortly after ketonuria onset.
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with the possible exception of a ketogenic diet"
explanation: >-
In the multicenter cohort, the ketogenic diet was the only modality with a
possible effect on shortening the acute phase.
- name: First-Line Immunotherapy
description: >-
First-line immunotherapy - high-dose corticosteroids, intravenous
immunoglobulin, and/or plasma exchange - is used acutely to suppress the
presumed immune-mediated process, though responses are frequently
incomplete.
therapeutic_modality: OTHER
target_mechanisms:
- target: Innate Neuroinflammatory Activation
treatment_effect: INHIBITS
description: >-
Broad immunosuppression aims to dampen the neuroinflammatory driver.
treatment_term:
preferred_term: Immunosuppressive Therapy
term:
id: NCIT:C15261
label: Immunosuppressive Therapy
evidence:
- reference: PMID:21883180
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients)"
explanation: >-
First-line immunotherapy (IVIG, steroids) is commonly used in FIRES,
although the cohort found limited evidence of efficacy for these acute-phase
modalities.
- reference: PMID:35997591
supports: SUPPORT
evidence_source: OTHER
snippet: "To develop consensus-based recommendations for the management of adult and paediatric patients with NORSE/FIRES based on best evidence and experience"
explanation: >-
International consensus recommendations exist for NORSE/FIRES management,
including acute immunotherapy.
- name: Anesthetic Burst-Suppression
description: >-
Continuous intravenous anesthetics (e.g., midazolam, barbiturates, ketamine)
are used to induce burst-suppression and control the super-refractory status
epilepticus in the intensive care unit; this is supportive seizure control
rather than disease-modifying.
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Super-Refractory Status Epilepticus
treatment_effect: INHIBITS
description: >-
Anesthetic burst-suppression suppresses ongoing status epilepticus.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:21883180
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "burst-suppression coma (BSC, 46 patients)"
explanation: >-
Anesthetic-induced burst-suppression coma was used to control the acute
status epilepticus in most patients in the cohort.
- name: Cannabidiol
description: >-
Pharmaceutical-grade cannabidiol has been reported to reduce seizures in
FIRES and is used as an adjunct in the chronic drug-resistant phase.
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Chronic Drug-Resistant Epilepsy and Neurocognitive Sequelae
treatment_effect: INHIBITS
description: >-
Cannabidiol reduces seizure burden as an adjunctive antiseizure agent.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: cannabidiol
term:
id: CHEBI:69478
label: cannabidiol
discussions:
- discussion_id: fires-il1-early-immunotherapy-window
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- "pathophysiology#Innate Neuroinflammatory Activation"
- "pathophysiology#Super-Refractory Status Epilepticus"
prompt: >-
FIRES is hypothesized to be driven by an IL-1-beta/IL-6 innate-immune
cytokine surge, and anakinra/tocilizumab appear more effective when started
early. Does early, mechanism-targeted cytokine blockade (versus escalating
anesthetics and later immunotherapy) shorten the super-refractory status
epilepticus and improve chronic-phase epilepsy and cognitive outcome?
rationale: >-
The cytokinopathy model predicts that early IL-1/IL-6 blockade should
interrupt the cascade before irreversible neuronal injury, but the evidence is
largely from case series and retrospective cohorts, and the optimal timing and
agent remain unestablished.
evidence:
- reference: PMID:27770579
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES"
explanation: >-
Cytokine normalization on anakinra motivates testing early
mechanism-targeted cytokine blockade against outcome.
proposed_experiments:
- experiment_id: fires-early-cytokine-blockade-trial
name: Early cytokine-blockade timing trial in FIRES
description: >-
In a multicenter FIRES registry/trial, compare time-to-resolution of
super-refractory status epilepticus and chronic-phase seizure/cognitive
outcomes by time from onset to initiation of IL-1/IL-6-targeted therapy.
readouts:
- name: Status-epilepticus duration and chronic outcome versus time-to-cytokine-blockade
target: "pathophysiology#Super-Refractory Status Epilepticus"
would_support:
- "pathophysiology#Innate Neuroinflammatory Activation"
- discussion_id: fires-genetic-susceptibility
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- "pathophysiology#Innate Neuroinflammatory Activation"
prompt: >-
Why does a common febrile illness trigger catastrophic FIRES in a previously
healthy child? Is there an underlying genetic predisposition of the innate
immune response (e.g., in the IL-1 pathway or other inflammasome/cytokine
genes) that determines susceptibility?
rationale: >-
FIRES strikes previously healthy children without an identified pathogen or
classic autoimmune antibody, suggesting a host-susceptibility factor. A
functional deficiency of endogenous IL-1RA (IL1RN) has been demonstrated in
small FIRES cohorts, but whether this is a reproducible, generalizable
susceptibility signature - and how it interacts with the febrile trigger -
remains open.
evidence:
- reference: PMID:30779222
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity"
explanation: >-
An IL1RN/IL-1RA functional-deficiency signature is the leading
host-susceptibility lead motivating this gap.
proposed_experiments:
- experiment_id: fires-host-susceptibility-genomics
name: Host innate-immune susceptibility genomics in FIRES
description: >-
Perform genomic/immunogenetic profiling (e.g., IL-1 pathway and
inflammasome genes) in a FIRES cohort versus controls to test for a
susceptibility signature.
readouts:
- name: Innate-immune genetic susceptibility signature
target: "pathophysiology#Innate Neuroinflammatory Activation"
would_support:
- "pathophysiology#Innate Neuroinflammatory Activation"
FIRES is a rare, catastrophic epileptic encephalopathy in which a previously healthy person — usually a school-age child — develops explosive, drug-resistant status epilepticus a few days after a banal, self-limited febrile illness (a cold, a stomach bug). The fever itself is gone or fading by the time the brain catches fire. There's no tumor, no stroke, no obvious infection in the brain, no metabolic crash to explain it. The seizures just won't stop, often for weeks to months, and survivors are almost always left with lasting epilepsy and cognitive damage.
The clean way to think about the naming, settled by the 2018 international consensus (Hirsch et al., Epilepsia 2018;59:739–744, doi:10.1111/epi.14016, verify PMID):
Quote (consensus framing, per NORSE Institute summary of Hirsch 2018): "FIRES is a subtype of NORSE that involves a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to the onset of refractory status epilepticus."
Key identifiers:
| System | ID |
|---|---|
| MONDO | MONDO:0015584 |
| Orphanet | ORPHA:163703 |
| ICD-10 | G40.5 (special epileptic syndromes) |
| ICD-11 | 8A63.Y (other specified status epilepticus) |
| GARD | 11005 |
| OMIM | none — no Mendelian OMIM entry (consistent with its non-Mendelian nature) |
Common synonyms / historical names (worth carrying as synonyms, because the older names encode obsolete assumptions):
- Fever-Induced Refractory Epileptic Encephalopathy in School-age children (FIRES — the original Nabbout acronym)
- Acute Encephalitis with Refractory Repetitive Partial Seizures (AERRPS, Japanese literature)
- Devastating Epileptic Encephalopathy in School-age Children (DESC)
- Idiopathic catastrophic epileptic encephalopathy; "new-onset cryptogenic febrile SE"
Data provenance: almost entirely disease-level aggregated from case reports and small case series — there is no large individual-patient EHR registry, and worldwide only ~on the order of 100+ well-characterized cases have been published. This scarcity is itself a load-bearing fact for every "frequency" and "prevalence" claim below.
Sources: Orphanet 163703, NORD, Hirsch 2018 consensus, Lit review PMC9756623.
Causal factors — the honest answer is "unknown trigger, stereotyped response." The leading model is that a nonspecific febrile infection acts as a trigger, not a cause, unmasking a runaway innate-immune / autoinflammatory cascade in the brain. Think of the fever as the match and a primed neuroinflammatory system as the dry grass — the fire's character comes from the grass, not the match. Most likely, per Orphanet, "FIRES is an immune-inflammatory-mediated epileptic encephalopathy, with a vicious circle of inflammation and hyperexcitability."
Genetic risk factors: No causal Mendelian gene. The candidate-gene study by Appenzeller et al. (2012, Dev Med Child Neurol; PMID:23066759) explicitly showed "FIRES is not caused by SCN1A, POLG, PCDH19 mutations or rare copy number variations." What does recur is susceptibility in innate-immune / cytokine genes: - IL1RN (IL-1 receptor antagonist gene) — a VNTR allele and a risk haplotype were over-represented in FIRES patients vs controls; the index anakinra-responder carried multiple IL1RN variants with reduced intracellular IL-1RA expression (Clarkson et al. 2019, Ann Neurol; PMID:30779222). - Emerging single reports of rare de novo variants in innate-immune/microglial genes — e.g., a de novo pathogenic CSF1R variant implicating microglial dysfunction (Fisher et al. 2025, Epilepsia, doi:10.1111/epi.18538, verify PMID). These are individual leads, not established causes.
Environmental / demographic risk factors: young school age (peak ~7–10 yr), possibly slight male predominance, and simply having a recent febrile infection. No occupational/toxic exposures implicated.
Protective factors: none established genetically or environmentally. Suggestively, the IL1RN findings imply that adequate endogenous IL-1RA function is protective and its functional deficiency is permissive — an inverted-protection framing rather than a discovered protective allele.
Gene–environment interaction is arguably the core of FIRES: a permissive innate-immune genotype (e.g., low-functioning IL-1RA) + a common febrile infection → uncontrolled IL-1β-driven neuroinflammation. This G×E convergence is the single most curation-worthy mechanistic claim.
Sources: Appenzeller 2012 PMID:23066759, Clarkson 2019 PMID:30779222, "Fighting autoinflammation in FIRES" PMID:35356746, Fisher 2025 CSF1R.
Clinical course runs in three phases (per lit review PMC9756623):
Prodromal phase — mild febrile illness (URI or GI), 1–2 days, then a symptom-free interval of 24 h–2 weeks.
Acute phase — the defining catastrophe: - Status epilepticus, refractory / super-refractory — HP:0002133 (Status epilepticus), with focal seizures with impaired awareness (HP:0002384) evolving to bilateral tonic-clonic seizures (HP:0002069); often multifocal with migrating perisylvian/fronto-temporal foci. Frequency: ~100% (defining feature). - Seizures broadly — HP:0001250. Frequency: obligate. - Encephalopathy / impaired consciousness — HP:0002383 (Focal-onset) / HP:0001259 (Coma) during barbiturate suppression. Frequency: very frequent. - Fever preceding — HP:0001945. Frequency: obligate by definition (in the preceding window). - Dysautonomia (tachycardia, blood pressure lability) during ICU course — HP:0011448 (Abnormal autonomic nervous system physiology). Occasional.
Chronic phase — near-universal in survivors: - Refractory/pharmacoresistant epilepsy — HP:0011171 (Refractory status is upstream) / HP:0002197 is not right; use HP:0001250 + intractability noted; Drug-resistant epilepsy maps well to HP:0011097 (Epileptic encephalopathy) as the overarching descriptor. Per PMC9756623: "among 66 of the 68 survived, 63 of them continued to have epilepsy refractory to any type of treatment." Frequency: ~90–95% of survivors. - Intellectual disability — HP:0001249. Roughly one-third normal/borderline, one-third mild–moderate ID, one-third severe ID/vegetative. Frequency: ~66–100% of survivors. - Cognitive/memory impairment — HP:0100543 (Cognitive impairment), esp. memory impairment HP:0002354 (mesial temporal injury). Very frequent. - Language impairment / regression — HP:0002463; speech regression HP:0001344. Frequent. - Behavioral / neuropsychiatric changes — HP:0000708 (Behavioral abnormality), including autistic features, ADHD-like symptoms, mood/psychiatric sequelae. Frequent. - Motor deficits — HP:0001324 (Muscle weakness) / HP:0002071 (Abnormality of extrapyramidal motor function); spasticity/ataxia in severe cases. Variable.
Laboratory phenotype: - CSF pleocytosis — mild lymphocytic, in >50% of patients (HP:0012229, Abnormal CSF protein/cellular content). - Elevated CSF & serum pro-inflammatory cytokines/chemokines (IL-6, IL-1β, IL-1RA, IL-8, CXCL/CCL chemokines) — the biochemical signature. - Usually normal glucose, negative viral PCR/cultures, negative or nonspecific autoantibodies.
Onset/severity/progression: onset acute/explosive, pediatric predominant (but any age per consensus); severity severe essentially by definition; acute phase episodic-to-continuous SE lasting weeks–months, then a chronic, often progressive-then-static deficit. QoL impact is profound — survivors frequently need lifelong care, special education, and have high caregiver burden; no FIRES-specific validated QoL instrument exists (generic pediatric epilepsy/QOLCE tools apply).
Sources: PMC9756623, Orphanet.
This section is where the template's gene-centric framing mostly does not apply, and that absence is itself the finding.
Ontology handles: gene IL1RN; process GO:0032611 (interleukin-1 beta production), GO:0004908 (interleukin-1 receptor activity), GO:0070498 (interleukin-1-mediated signaling pathway).
Sources: Clarkson 2019 PMID:30779222, Appenzeller 2012 PMID:23066759.
The environmental story is thin by design: FIRES is defined partly by the absence of a clear structural/toxic/metabolic cause.
This is the heart of the entry and where the causal chain lives. Best current model — a self-amplifying innate-immune ↔ hyperexcitability loop:
Causal chain (upstream → downstream):
Supporting quotes: - "Elevated IL-6 levels in the central nervous system worsen neuroinflammation by activating microglia and astrocytes, releasing pro-inflammatory cytokines, and weakening the blood-brain barrier." - "FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity" (Clarkson 2019, PMID:30779222).
Cell types (CL): microglial cell CL:0000129; astrocyte CL:0000127; central nervous system neuron / glutamatergic neuron CL:0000679; hippocampal pyramidal neuron; peripheral monocyte/macrophage CL:0000235 (infiltrating).
Biological processes (GO): GO:0006954 (inflammatory response); GO:0002526 (acute inflammatory response); GO:0070498 (IL-1-mediated signaling); GO:0032635/GO:0032611 (IL-6 / IL-1β production); GO:0001774 (microglial activation); GO:0060291/excitatory synaptic plasticity; GO:0007268 (chemical synaptic transmission); BBB dysfunction (GO:0043114 regulation of vascular permeability).
Immune involvement: predominantly innate/autoinflammatory (IL-1/IL-6 axis, microglia), not classic adaptive autoimmunity — antibodies usually absent. This is why IL-1 blockade (anakinra) and IL-6R blockade (tocilizumab) are mechanistically rational and empirically the most promising immunotherapies.
Molecular profiling: the reproducible signal is a CSF/serum cytokine-chemokine signature (↑IL-6, ↑IL-1RA, ↑IL-1β, ↑IL-8, ↑CXCL10, ↑CCL chemokines). No robust FIRES-specific transcriptomic/proteomic/metabolomic dataset yet — a genuine knowledge gap worth a discussions: KNOWLEDGE_GAP note.
Sources: "Fighting autoinflammation in FIRES" PMID:35356746, Clarkson 2019 PMID:30779222, IL-6 neuro review PMC11249726, NORSE immune dysregulation review.
Sources: PMC9756623.
Sources: Wickstrom 2022 consensus PMID:35951466, PMC9756623.
Prevalence: measure_type: POINT_PREVALENCE, prevalence_class: BAND_1_9_PER_1000000 or BELOW_1_IN_1000000 depending on framing; rate_per_100000 ≈ 1.0 (prevalence) — and a separate ANNUAL_INCIDENCE record at rate_per_100000 ≈ 0.1 (1/1,000,000). Do not conflate the two.Sources: Orphanet, Dovepress prevalence/impact review.
FIRES is fundamentally a diagnosis of exclusion + a compatible clinical picture (refractory SE after recent fever, no cause found). Consensus (Wickstrom 2022, PMID:35951466) emphasizes broad, rapid workup.
Sources: Wickstrom 2022 PMID:35951466, PMC9756623.
Blunt truth: FIRES is one of the worst outcomes in pediatric neurology.
Sources: Orphanet, NORD, PMC9756623.
No cure; management is a two-front war — stop the seizures and cool the inflammation — with early, aggressive escalation. The 2022 international consensus (Wickstrom et al., PMID:35951466, 85 consensus statements) is the anchor.
A. Anti-seizure / anesthetic (acute SE control) - Standard SE ladder: benzodiazepines → IV ASMs (levetiracetam, valproate, phenytoin/fosphenytoin) → anesthetic/burst-suppression coma (midazolam, barbiturates/pentobarbital, ketamine, propofol). Caveat: prolonged barbiturate coma correlates with worse cognition — a therapy whose cure edges into harm. - MAXO: MAXO:0000058 (pharmacotherapy) / antiseizure pharmacotherapy; anesthesia. - Cannabidiol (Epidiolex): promising in both phases — case series of 7 children, 6/7 improved in seizure frequency/duration (Gofshteyn et al. 2017, J Child Neurol; PMID:27655472); acute-phase reports of SE resolution within days (Fetta 2023, Epilepsia Open, doi:10.1002/epi4.12740, verify PMID). CHEBI: cannabidiol CHEBI:69478. - Other ASMs reported ad hoc (cenobamate, perampanel, topiramate) in the chronic phase — anecdotal.
B. Ketogenic diet (KD) — a signature FIRES therapy - Landmark: Nabbout et al. 2010, Epilepsia (doi:10.1111/j.1528-1167.2010.02703.x, verify PMID) — 4:1 KD in 9 FIRES children, efficacious in 7, with seizure cessation 2–4 days after ketonuria / 4–6 days after diet onset. Now a recommended early adjunct (watch for propofol interaction → propofol infusion syndrome). MAXO: MAXO:0000088 (dietary intervention) / ketogenic diet.
C. Immunotherapy (mechanistically the most rational) - First-line, start within ~72 h: high-dose corticosteroids (MAXO/CHEBI corticosteroid), IVIG, and/or plasma exchange. MAXO: MAXO:0000759 (immunosuppressive therapy); plasmapheresis. - Second-line, escalate early in cryptogenic FIRES: - Anakinra (recombinant IL-1 receptor antagonist) — the most evidence-backed targeted therapy, born from the mechanism itself. First reported by Kenney-Jung et al. 2016, Ann Neurol (doi:10.1002/ana.24806, verify PMID): CSF cytokines normalized on treatment. In one series, 11/15 children had >50% seizure reduction at 1 week (PMC9756623); early use → shorter ICU stay. Long-term neuropsych outcomes can still be poor despite anakinra (Frontiers Neurol 2023). - Tocilizumab (IL-6 receptor monoclonal antibody) — effective in some anakinra-refractory cases (Stredny et al. 2020, Child Neurol Open, doi:10.1177/2329048X20979253, verify PMID); and vice versa — anakinra works in some tocilizumab-refractory cases even with normal IL-1β (Frontiers Immunol 2026). MAXO: MAXO:0000759 immunomodulation; therapeutic_modality: MONOCLONAL_ANTIBODY for tocilizumab. - Chronic-phase case series: anakinra/tocilizumab gave partial seizure reduction (20–50%) in some, no seizure-freedom (Seizure 2022, PMID:35759951). - Others (rituximab, tacrolimus, canakinumab, cyclophosphamide) — inconsistent/unclear benefit.
D. Other / experimental: vagus nerve stimulation and epilepsy surgery in selected chronic drug-resistant cases; therapeutic hypothermia (largely abandoned); intrathecal/other anti-cytokine strategies under study. Active clinical trials exist (e.g., KD for SRSE, NCT07496749 — verify) — search ClinicalTrials.gov for current anakinra/tocilizumab/KD FIRES trials.
Pharmacogenomics: none FIRES-specific; the closest thing to "genotype-guided therapy" is the conceptual match of IL-1RA-deficiency → anakinra, i.e., mechanism-guided rather than pharmacogenomic.
Sources: Wickstrom 2022 PMID:35951466, Kenney-Jung 2016, Nabbout 2010 KD, Gofshteyn 2017 CBD PMID:27655472, Anakinra long-term outcomes, Chronic-phase series PMID:35759951.
Largely not applicable / not feasible — you can't screen for or vaccinate against a syndrome whose trigger is "some ordinary fever" in a genetically-unpredictable host.
Sources: Wickstrom 2022 PMID:35951466.
No faithful animal model of FIRES exists — a genuine translational gap, and worth a discussions: HUMAN_MODEL_MISMATCH entry rather than a claim of recapitulation.
Resources: MGI (Il1rn, Il6 alleles), rodent SE/neuroinflammation literature.
conforms_to target is the epilepsy convergence module — epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance — with FIRES supplying the upstream inflammatory driver (IL-1β/IL-6 → NMDA potentiation + GABA suppression) rather than a channel variant. Consider whether a dedicated neuroinflammation/autoinflammatory-seizure module is warranted; if one is ever built, FIRES + antibody-mediated NORSE would be natural conformers.target_mechanisms.Prevalence records (point prevalence ~1/100,000 vs annual incidence ~1/1,000,000) — don't merge; different measure_type.just fetch-reference on each and verify snippets before committing.Primary sources cited: Hirsch 2018 consensus (Epilepsia) · Wickstrom 2022 management consensus (PMID:35951466) · Clarkson 2019 IL-1RA deficiency (PMID:30779222) · Appenzeller 2012 gene-negative (PMID:23066759) · Kenney-Jung 2016 anakinra · Nabbout 2010 ketogenic diet · Gofshteyn 2017 cannabidiol (PMID:27655472) · Chronic-phase anakinra/tocilizumab series (PMID:35759951) · "Fighting autoinflammation in FIRES" (PMID:35356746) · Fisher 2025 CSF1R (Epilepsia) · Lit review + 2 cases (PMC9756623) · Orphanet 163703 · NORD/MONDO FIRES.
That's the whole map, Harry. The one-sentence version if you're skimming: FIRES is a fever that lights a match in a brain whose anti-inflammatory fire extinguisher (IL-1RA) is functionally busted — so the innate-immune blaze and the seizures feed each other into weeks of unstoppable status epilepticus, and the survivors pay for it for life. The whole thing points at IL-1/IL-6 blockade as the rational therapy, which is exactly where the anakinra/tocilizumab evidence is pooling. Curate it as an inflammatory epileptic encephalopathy hanging off the E/I-imbalance module, not as a gene disorder — there is no gene.