Nerve Agent Poisoning

⚙

Pathophysiology

8

Acetylcholinesterase Inhibition

Organophosphorus nerve agents (sarin, soman, tabun, cyclosarin, VX and the Novichok agents) are extremely potent inhibitors of acetylcholinesterase (AChE). They phosphylate the catalytic serine of the enzyme, abolishing its ability to hydrolyse acetylcholine throughout the central and peripheral nervous systems.

acetylcholine catabolic process GO:0006581 ↓ DECREASED

Downstream

Aging of the Nerve Agent-AChE Adduct

Synaptic Acetylcholine Accumulation

Show evidence (2 references)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The major mechanism of acute toxicity is the irreversible inhibition of acetylcholinesterase."

Identifies AChE inhibition as the primary mechanism of acute nerve agent toxicity.

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The major mechanism of OPC toxicity is through inhibition of acetylcholinesterase in neuronal synapses leading to excess acetylcholine and overstimulation of target organs."

States the AChE-inhibition mechanism shared by the organophosphorus nerve agents.

Aging of the Nerve Agent-AChE Adduct

The phosphylated enzyme loses an alkyl group ("aging"), converting the inhibited AChE into an oxime-refractory form; once aging has occurred the inhibition is permanent. The aging rate is agent-specific, and this irreversibility is what limits the window during which oxime reactivators can work — the feature that most sharply separates nerve agents from most insecticidal organophosphates.

Downstream

Synaptic Acetylcholine Accumulation

Show evidence (2 references)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"the covalent bond between the active site and the OP nerve agent stabilizes by removal of an alkyl group, a process called aging"

Describes the dealkylation that renders AChE inhibition irreversible.

PMID:18555982 SUPPORT DIRECT In Vitro

"Aging rate constants of GF-, GD-, and VR-inhibited monkey AChEs were very similar to human AChE except for GF-inhibited monkey AChEs, which aged 2-3 times faster than the human enzyme"

Measures agent-specific aging rate constants for nerve-agent-inhibited AChE, establishing aging as a quantifiable, agent-dependent process.

Synaptic Acetylcholine Accumulation

With AChE inactivated, acetylcholine accumulates at muscarinic and nicotinic synapses throughout the peripheral and central nervous systems, producing sustained cholinergic receptor overstimulation.

Downstream

Muscarinic Receptor Overstimulation

Nicotinic Receptor Overstimulation

Central Cholinergic Overstimulation

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Acetylcholinesterase inhibition results in the accumulation of excessive acetylcholine levels in synapses, leading to progression of toxic signs including hypersecretions, tremors, status epilepticus, respiratory distress, and death."

Synaptic acetylcholine accumulation is the step driving the downstream toxidrome.

Muscarinic Receptor Overstimulation

Excess acetylcholine at peripheral muscarinic receptors drives glandular hypersecretion and smooth-muscle effects: miosis, rhinorrhoea, lacrimation, salivation, bronchorrhoea, bronchospasm, vomiting and diarrhoea.

Downstream

Miosis

Rhinorrhea

Hypersalivation

Diarrhea

Vomiting

Bronchospasm

Bronchorrhea

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."

Enumerates the muscarinic toxidrome produced by cholinergic overstimulation.

Nicotinic Receptor Overstimulation

Acetylcholine excess at nicotinic receptors of the neuromuscular junction first causes fasciculations and then depolarising blockade with muscle weakness and flaccid paralysis, including the diaphragm; respiratory-muscle paralysis is one route to respiratory failure.

Downstream

Muscle fasciculation

Muscle weakness

Respiratory failure

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Nicotinic symptoms such as paralysis and fasciculations may also occur."

The nicotinic toxidrome produces fasciculations and paralysis.

Central Cholinergic Overstimulation

Central cholinergic overstimulation initiates seizures that can progress to status epilepticus, together with altered mental status, loss of consciousness and central respiratory depression.

Downstream

Seizure

Coma

Respiratory failure

Glutamatergic Excitotoxicity

Show evidence (2 references)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention."

The central toxidrome comprises seizures, altered mental status and apnoea.

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"acetylcholinesterase inhibition results in the overactivation of muscarinic receptors leading to the initiation of status epilepticus"

Central cholinergic overactivation initiates status epilepticus.

Glutamatergic Excitotoxicity

Sustained status epilepticus is maintained by a massive release of glutamate, which drives NMDA-receptor-mediated excitotoxic neuronal injury. This is the bridge between the acute cholinergic crisis and the lasting neuropathology, and the reason seizures must be stopped quickly.

glutamate secretion GO:0014047 ↑ INCREASED NMDA receptor-mediated glutamate signalling GO:0007215 ↑ INCREASED

Downstream

Seizure-Driven Limbic Neurodegeneration

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Excessive synaptic acetylcholine levels cause a massive release of glutamate which in turn, sustains and maintains status epilepticus"

Cholinergic overstimulation drives a glutamate surge that sustains status epilepticus.

Seizure-Driven Limbic Neurodegeneration

Prolonged seizures produce neuronal death concentrated in the amygdala and other limbic and cortical regions. This neuropathology underlies the long-term cognitive and neuropsychiatric sequelae seen in survivors.

neuron death GO:0051402 ↑ INCREASED

Downstream

Memory impairment

Anxiety

Show evidence (2 references)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Prolonged seizures are responsible for the neuropathology."

Prolonged nerve-agent seizures cause the neuropathology.

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The brain region that shows the most severe damage is the amygdala, followed by the piriform cortex, hippocampus, cortex, thalamus, and caudate/putamen."

Localises the seizure-driven neurodegeneration to limbic and cortical regions.

⬡

Pathograph

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Phenotypes

14

Digestive 2

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."

Diarrhea is part of the muscarinic toxidrome.

Vomiting HP:0002013

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."

Emesis (vomiting) is part of the muscarinic toxidrome.

Eye 1

Miosis HP:0000616

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents."

Miosis is the most common clinical finding after acute nerve agent exposure.

Head and Neck 1

Hypersalivation Excessive salivation HP:0003781

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."

Salivation is part of the muscarinic toxidrome.

Musculoskeletal 1

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Effects at the neuromuscular junction cause weakness, fasciculations, and eventually paralysis."

Acute nerve-agent effect at the neuromuscular junction includes weakness and paralysis.

Nervous System 5

Muscle fasciculation Fasciculations HP:0002380

Show evidence (2 references)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Nicotinic symptoms such as paralysis and fasciculations may also occur."

Fasciculations are a nicotinic sign of nerve agent toxicity.

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Effects at the neuromuscular junction cause weakness, fasciculations, and eventually paralysis."

Acute nerve-agent effect at the neuromuscular junction includes fasciculations.

Seizure HP:0001250

Show evidence (1 reference)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention."

Seizures are a central manifestation of nerve agent toxicity.

Coma HP:0001259

Show evidence (1 reference)

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Central effects include altered behavior and mental status, loss of consciousness, seizures, or apnea."

Acute central nerve-agent toxicity includes loss of consciousness, the severe end of which is coma.

Memory impairment HP:0002354

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Years after exposure to sarin, victims of the Tokyo subway attack presented with significant declines in psychomotor and memory functions"

Tokyo subway sarin survivors showed long-term declines in memory function.

Anxiety HP:0000739

Show evidence (1 reference)

PMID:21783510 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"of 303 respondents, 45% still had some symptoms including eye problems, easy fatigability, headache, and fear."

Persistent fear among one-year survivors supports lasting anxiety; graded indirect as fear is the quoted term.

Respiratory 3

Rhinorrhea HP:0031417

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents."

Rhinorrhea is named co-equal with miosis as the most common acute finding.

Bronchospasm Wheezing HP:0030828

Sequelae: Respiratory failure

Show evidence (1 reference)

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."

Names bronchospasm among the muscarinic (parasympathetic) effects of nerve agents.

Respiratory failure HP:0002878

Show evidence (2 references)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"generalized signs of toxicity including status epilepticus, defecation, miosis, bronchospasm, bronchorrhea, paralysis and respiratory failure"

Respiratory failure is a terminal manifestation of nerve agent poisoning.

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Most deaths are due to respiratory failure."

Respiratory failure is the leading cause of death.

Other 1

Bronchorrhea

No exact HPO term for bronchorrhea (excessive bronchial/airway secretions) was found; the ontology term is omitted pending a New Term Request, following the sibling Organophosphate_Poisoning entry.

Sequelae: Respiratory failure

Show evidence (1 reference)

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."

Names bronchorrhea among the muscarinic (parasympathetic) effects of nerve agents.

💊

Medical Actions

4

Atropine

Action: Pharmacotherapy NCIT:C15986

Agent: atropine CHEBI:16684

Platform: Small molecule

Competitive muscarinic antagonist that reverses the muscarinic (secretory/bronchospastic) effects; titrated to drying of secretions.

Mechanism Target:

Muscarinic Receptor Overstimulation

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Standard-of-care treatment for OP nerve agent acute exposure includes atropine, a muscarinic antagonist, pralidoxime (2-PAM), an oxime that regenerates acetycholinesterase activity in those molecules that are not aged, and diazepam, a benzodiazepine to stop/attenuate seizures."

Atropine is the standard-of-care muscarinic antagonist for nerve agent poisoning.

Oxime reactivator (pralidoxime)

Action: Pharmacotherapy NCIT:C15986

Agent: pralidoxime CHEBI:8354

Platform: Small molecule

Reactivates inhibited acetylcholinesterase by displacing the nerve agent from the catalytic serine; effective only in enzyme molecules that have not yet aged.

Mechanism Target:

Acetylcholinesterase Inhibition

Show evidence (2 references)

PMID:18555982 SUPPORT DIRECT In Vitro

"the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited acetylcholinesterase (AChE)"

Oxime benefit depends on reactivating inhibited AChE, the mechanism this treatment targets.

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"pralidoxime (2-PAM), an oxime that regenerates acetycholinesterase activity in those molecules that are not aged"

Pralidoxime regenerates AChE but only before the adduct ages.

Benzodiazepine

Action: Pharmacotherapy NCIT:C15986

Agent: diazepam CHEBI:49575

Platform: Small molecule

First-line anticonvulsant for nerve-agent seizures and status epilepticus; by stopping seizures it also limits the glutamatergic excitotoxicity that drives neuropathology. Efficacy declines the longer administration is delayed.

Mechanism Target:

Central Cholinergic Overstimulation

Glutamatergic Excitotoxicity

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Anticonvulsants such as benzodiazepines decrease seizure activity and improve outcome, but their efficacy depends upon the administration time after exposure to the nerve agent."

Benzodiazepines control nerve-agent seizures, with time-dependent efficacy.

Decontamination and supportive care

Action: Supportive Care NCIT:C15747

Removal from source, skin/clothing and ocular decontamination, airway management and mechanical ventilation.

Mechanism Target:

Respiratory failure

Show evidence (2 references)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Treatment includes early airway and ventilatory support as well as antidotal therapy with atropine, pralidoxime, and diazepam."

Airway and ventilatory support underpin management of respiratory failure.

PMID:15979676 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Preparation for a large-scale chemical attack by terrorists requires the prior establishment of a detailed decontamination plan"

Decontamination planning is a core response to mass nerve agent exposure.

🌍

Environmental Factors

1

Nerve agent vapour or liquid exposure

Nerve agents are released deliberately as vapour or liquid in warfare, terrorism and targeted assassination; exposure is by inhalation and percutaneous absorption.

Show evidence (2 references)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"These compounds quickly and efficiently penetrate the human body via the skin, inhalation, and through the bloodstream."

Establishes the dermal and inhalational routes of nerve agent exposure.

PMID:32198755 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment."

Documents real-world warfare, assassination and terrorism exposure incidents.

Mechanism Target:

TRIGGERS Acetylcholinesterase Inhibition — Absorbed nerve agent reaches synaptic acetylcholinesterase and inhibits it.

Show evidence (1 reference)

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Nerve agents selectively target and irreversibly inhibit acetylcholinesterase (AChE)"

Absorbed nerve agent inhibits acetylcholinesterase, initiating the toxidrome.

🔬

Biochemical Markers

1

Blood cholinesterase activity (DECREASED)

Show evidence (3 references)

PMID:21783510 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Reduction in plasma cholinesterase (ChE) activity was generally associated with the severity of acute signs of toxicity."

In Tokyo subway sarin victims, lower plasma cholinesterase activity tracked with greater acute toxicity severity.

PMID:21783510 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"With time and treatment, the value rose quickly."

Cholinesterase activity recovers with treatment and time, supporting its use for monitoring.

PMID:32198755 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources."

Cholinesterase status guides oxime therapy duration and success.

📈

Progression

2

Acute cholinergic crisis

Age: Minutes to hours after exposure

Onset is within seconds to minutes after vapour exposure and can be delayed after dermal exposure. The cholinergic crisis (muscarinic, nicotinic and central overstimulation) evolves rapidly, and death in this phase is principally from respiratory failure. Surviving the first minutes of a vapour attack strongly predicts survival.

Show evidence (1 reference)

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If victims can survive the first 15 to 20 min of a vapor attack, they will likely live."

Characterises the tempo and survivability of the acute phase.

Long-term neuropsychiatric sequelae

Age: Months to years after exposure

Survivors, particularly after status epilepticus, can be left with persistent neurologic, cognitive and behavioural deficits and structural brain changes. One year after the Tokyo subway attack, 45% of responding survivors still reported symptoms.

Show evidence (2 references)

PMID:21783510 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"of 303 respondents, 45% still had some symptoms including eye problems, easy fatigability, headache, and fear."

Documents persistent symptoms one year after acute sarin exposure.

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Recent studies document long-term neurologic and behavior deficits, and technological advances demonstrate structural brain changes on magnetic resonance imaging."

Documents long-term neurologic/behavioural deficits and structural brain changes.

📊

Prevalence

1

Incident-based (chemical-warfare and terrorism events)

Cases In Literature Not yet documented

Occurrence is incident-based rather than endemic, so no population rate is defensible. The 1995 Tokyo subway sarin attack brought 640 patients to a single hospital on the day of the attack; other mass-exposure events include Matsumoto (1994), Halabja (1988) and Ghouta/Syria (2013).

Show evidence (1 reference)

PMID:21783510 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The St. Luke's International Hospital received 640 patients on the day of the attack."

Documents the incident-based case count from the Tokyo subway sarin attack.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Nerve Agent Poisoning:

Organophosphate (pesticide) poisoning MONDO:0800386

Distinguishing Features

Both are organophosphorus poisonings acting by acetylcholinesterase inhibition and share the cholinergic toxidrome, so they are not distinguished by a different mechanism. What separates them is pharmacodynamic: nerve agents are military-grade compounds of far greater potency, and their inhibited enzyme can age to an oxime-refractory state that collapses the therapeutic window for reactivators. The sibling entry Organophosphate_Poisoning models insecticidal organophosphorus poisoning, which already represents nerve-agent exposure as one environmental route into the same pathway; whether these should remain separate Disease entries, become a has_subtypes stratum, or be joined by a covering Grouping is a scope decision for a maintainer.

Show evidence (3 references)

PMID:16168308 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The organic phosphorous compounds (OPC) include both the military grade nerve agents and the organic phosphorous pesticides."

Nerve agents and organophosphate pesticides are the two members of the same organophosphorus class, differing as military-grade versus agricultural agents.

PMID:30159887 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Nerve agents are organophosphate (OP) compounds and among the most powerful poisons known to man."

Supports the far greater potency of nerve agents relative to agricultural organophosphates.

PMID:16945386 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Oximes like pralidoxime salvage acetylcholine esterase by "prying off" NA, provided the attachment has not "aged" to an irreversible bond."

Supports the aging-dependent collapse of the oxime window as the pharmacodynamic distinction.

{ }

Source YAML

click to show

name: Nerve Agent Poisoning
creation_date: "2026-10-03T00:00:00Z"
category: Environmental
synonyms:
- nerve gas poisoning
- organophosphorus nerve agent poisoning
- chemical warfare nerve agent toxicity
description: >-
  Nerve agent poisoning is acute organophosphorus cholinergic toxicity caused by
  the chemical-warfare nerve agents (sarin, soman, tabun, cyclosarin, VX and the
  Novichok agents). These extremely potent compounds inhibit acetylcholinesterase,
  flooding muscarinic, nicotinic and central synapses with acetylcholine and
  producing a cholinergic crisis — miosis, hypersecretion, bronchospasm,
  fasciculations, paralysis, seizures and respiratory failure — within minutes of
  inhalational or dermal exposure. Death is principally respiratory. Survivors of
  the acute phase, particularly after status epilepticus, can be left with
  long-term neuropsychiatric and cognitive sequelae. It is a sibling of
  organophosphate (pesticide) poisoning; the clinically decisive difference is the
  rapid, oxime-refractory aging of the inhibited enzyme.
disease_term:
  preferred_term: nerve agent poisoning
  term:
    id: MONDO:0100331
    label: nerve agent poisoning
parents:
- poisoning
pathophysiology:
- name: Acetylcholinesterase Inhibition
  biological_scale: MOLECULAR
  description: >-
    Organophosphorus nerve agents (sarin, soman, tabun, cyclosarin, VX and the
    Novichok agents) are extremely potent inhibitors of acetylcholinesterase
    (AChE). They phosphylate the catalytic serine of the enzyme, abolishing its
    ability to hydrolyse acetylcholine throughout the central and peripheral
    nervous systems.
  biological_processes:
  - preferred_term: acetylcholine catabolic process
    modifier: DECREASED
    term:
      id: GO:0006581
      label: acetylcholine catabolic process
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The major mechanism of acute toxicity is the irreversible inhibition of acetylcholinesterase."
    explanation: Identifies AChE inhibition as the primary mechanism of acute nerve agent toxicity.
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The major mechanism of OPC toxicity is through inhibition of acetylcholinesterase in neuronal synapses leading to excess acetylcholine and overstimulation of target organs."
    explanation: States the AChE-inhibition mechanism shared by the organophosphorus nerve agents.
  downstream:
  - target: Aging of the Nerve Agent-AChE Adduct
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30159887
      reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: "over time the covalent bond between the active site and the OP nerve agent stabilizes by removal of an alkyl group"
      explanation: The inhibited enzyme progresses to the aged adduct over time.
  - target: Synaptic Acetylcholine Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30159887
      reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: "Acetylcholinesterase inhibition results in the accumulation of excessive acetylcholine levels in synapses"
      explanation: AChE inhibition directly causes synaptic acetylcholine to accumulate.
- name: Aging of the Nerve Agent-AChE Adduct
  biological_scale: MOLECULAR
  description: >-
    The phosphylated enzyme loses an alkyl group ("aging"), converting the
    inhibited AChE into an oxime-refractory form; once aging has occurred the
    inhibition is permanent. The aging rate is agent-specific, and this
    irreversibility is what limits the window during which oxime reactivators can
    work — the feature that most sharply separates nerve agents from most
    insecticidal organophosphates.
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "the covalent bond between the active site and the OP nerve agent stabilizes by removal of an alkyl group, a process called aging"
    explanation: Describes the dealkylation that renders AChE inhibition irreversible.
  - reference: PMID:18555982
    reference_title: "Comparison of oxime reactivation and aging of nerve agent-inhibited monkey and human acetylcholinesterases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Aging rate constants of GF-, GD-, and VR-inhibited monkey AChEs were very similar to human AChE except for GF-inhibited monkey AChEs, which aged 2-3 times faster than the human enzyme"
    explanation: Measures agent-specific aging rate constants for nerve-agent-inhibited AChE, establishing aging as a quantifiable, agent-dependent process.
  downstream:
  - target: Synaptic Acetylcholine Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Synaptic Acetylcholine Accumulation
  biological_scale: CELLULAR
  description: >-
    With AChE inactivated, acetylcholine accumulates at muscarinic and nicotinic
    synapses throughout the peripheral and central nervous systems, producing
    sustained cholinergic receptor overstimulation.
  chemical_entities:
  - preferred_term: acetylcholine
    modifier: INCREASED
    term:
      id: CHEBI:15355
      label: acetylcholine
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Acetylcholinesterase inhibition results in the accumulation of excessive acetylcholine levels in synapses, leading to progression of toxic signs including hypersecretions, tremors, status epilepticus, respiratory distress, and death."
    explanation: Synaptic acetylcholine accumulation is the step driving the downstream toxidrome.
  downstream:
  - target: Muscarinic Receptor Overstimulation
    causal_link_type: DIRECT
  - target: Nicotinic Receptor Overstimulation
    causal_link_type: DIRECT
  - target: Central Cholinergic Overstimulation
    causal_link_type: DIRECT
- name: Muscarinic Receptor Overstimulation
  biological_scale: ORGANISM
  description: >-
    Excess acetylcholine at peripheral muscarinic receptors drives glandular
    hypersecretion and smooth-muscle effects: miosis, rhinorrhoea, lacrimation,
    salivation, bronchorrhoea, bronchospasm, vomiting and diarrhoea.
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."
    explanation: Enumerates the muscarinic toxidrome produced by cholinergic overstimulation.
  downstream:
  - target: Miosis
    causal_link_type: DIRECT
  - target: Rhinorrhea
    causal_link_type: DIRECT
  - target: Hypersalivation
    causal_link_type: DIRECT
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Vomiting
    causal_link_type: DIRECT
  - target: Bronchospasm
    causal_link_type: DIRECT
  - target: Bronchorrhea
    causal_link_type: DIRECT
- name: Nicotinic Receptor Overstimulation
  biological_scale: ORGANISM
  description: >-
    Acetylcholine excess at nicotinic receptors of the neuromuscular junction
    first causes fasciculations and then depolarising blockade with muscle
    weakness and flaccid paralysis, including the diaphragm; respiratory-muscle
    paralysis is one route to respiratory failure.
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Nicotinic symptoms such as paralysis and fasciculations may also occur."
    explanation: The nicotinic toxidrome produces fasciculations and paralysis.
  downstream:
  - target: Muscle fasciculation
    causal_link_type: DIRECT
  - target: Muscle weakness
    causal_link_type: DIRECT
  - target: Respiratory failure
    causal_link_type: DIRECT
- name: Central Cholinergic Overstimulation
  biological_scale: ORGANISM
  description: >-
    Central cholinergic overstimulation initiates seizures that can progress to
    status epilepticus, together with altered mental status, loss of
    consciousness and central respiratory depression.
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention."
    explanation: The central toxidrome comprises seizures, altered mental status and apnoea.
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "acetylcholinesterase inhibition results in the overactivation of muscarinic receptors leading to the initiation of status epilepticus"
    explanation: Central cholinergic overactivation initiates status epilepticus.
  downstream:
  - target: Seizure
    causal_link_type: DIRECT
  - target: Coma
    causal_link_type: DIRECT
  - target: Respiratory failure
    causal_link_type: DIRECT
  - target: Glutamatergic Excitotoxicity
    causal_link_type: DIRECT
- name: Glutamatergic Excitotoxicity
  biological_scale: CELLULAR
  description: >-
    Sustained status epilepticus is maintained by a massive release of glutamate,
    which drives NMDA-receptor-mediated excitotoxic neuronal injury. This is the
    bridge between the acute cholinergic crisis and the lasting neuropathology,
    and the reason seizures must be stopped quickly.
  biological_processes:
  - preferred_term: glutamate secretion
    modifier: INCREASED
    term:
      id: GO:0014047
      label: glutamate secretion
  - preferred_term: NMDA receptor-mediated glutamate signalling
    modifier: INCREASED
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Excessive synaptic acetylcholine levels cause a massive release of glutamate which in turn, sustains and maintains status epilepticus"
    explanation: Cholinergic overstimulation drives a glutamate surge that sustains status epilepticus.
  downstream:
  - target: Seizure-Driven Limbic Neurodegeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30159887
      reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: "resulting in hypoxic-ischemic neuronal cell death via N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity"
      explanation: Glutamate excitotoxicity causes NMDA-mediated neuronal death.
- name: Seizure-Driven Limbic Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Prolonged seizures produce neuronal death concentrated in the amygdala and
    other limbic and cortical regions. This neuropathology underlies the
    long-term cognitive and neuropsychiatric sequelae seen in survivors.
  biological_processes:
  - preferred_term: neuron death
    modifier: INCREASED
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Prolonged seizures are responsible for the neuropathology."
    explanation: Prolonged nerve-agent seizures cause the neuropathology.
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The brain region that shows the most severe damage is the amygdala, followed by the piriform cortex, hippocampus, cortex, thalamus, and caudate/putamen."
    explanation: Localises the seizure-driven neurodegeneration to limbic and cortical regions.
  downstream:
  - target: Memory impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Anxiety
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Miosis
  phenotype_term:
    preferred_term: Miosis
    term:
      id: HP:0000616
      label: Miosis
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents."
    explanation: Miosis is the most common clinical finding after acute nerve agent exposure.
- name: Rhinorrhea
  phenotype_term:
    preferred_term: Rhinorrhea
    term:
      id: HP:0031417
      label: Rhinorrhea
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents."
    explanation: Rhinorrhea is named co-equal with miosis as the most common acute finding.
- name: Hypersalivation
  phenotype_term:
    preferred_term: Hypersalivation
    term:
      id: HP:0003781
      label: Excessive salivation
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."
    explanation: Salivation is part of the muscarinic toxidrome.
- name: Diarrhea
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."
    explanation: Diarrhea is part of the muscarinic toxidrome.
- name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation."
    explanation: Emesis (vomiting) is part of the muscarinic toxidrome.
- name: Bronchospasm
  description: >-
    Muscarinic bronchoconstriction (bronchospasm, clinically wheezing) is a
    muscarinic driver of respiratory compromise.
  phenotype_term:
    preferred_term: bronchospasm
    term:
      id: HP:0030828
      label: Wheezing
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
    explanation: Names bronchospasm among the muscarinic (parasympathetic) effects of nerve agents.
  sequelae:
  - target: Respiratory failure
- name: Bronchorrhea
  description: >-
    Muscarinic bronchorrhea (excessive airway secretions) is, with bronchospasm,
    a leading contributor to the respiratory failure that causes most deaths.
  phenotype_term:
    preferred_term: bronchorrhea
  notes: >-
    No exact HPO term for bronchorrhea (excessive bronchial/airway secretions)
    was found; the ontology term is omitted pending a New Term Request, following
    the sibling Organophosphate_Poisoning entry.
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
    explanation: Names bronchorrhea among the muscarinic (parasympathetic) effects of nerve agents.
  sequelae:
  - target: Respiratory failure
- name: Muscle fasciculation
  phenotype_term:
    preferred_term: Muscle fasciculation
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Nicotinic symptoms such as paralysis and fasciculations may also occur."
    explanation: Fasciculations are a nicotinic sign of nerve agent toxicity.
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Effects at the neuromuscular junction cause weakness, fasciculations, and eventually paralysis."
    explanation: Acute nerve-agent effect at the neuromuscular junction includes fasciculations.
- name: Muscle weakness
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Effects at the neuromuscular junction cause weakness, fasciculations, and eventually paralysis."
    explanation: Acute nerve-agent effect at the neuromuscular junction includes weakness and paralysis.
- name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention."
    explanation: Seizures are a central manifestation of nerve agent toxicity.
- name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Central effects include altered behavior and mental status, loss of consciousness, seizures, or apnea."
    explanation: Acute central nerve-agent toxicity includes loss of consciousness, the severe end of which is coma.
- name: Respiratory failure
  description: >-
    Death from nerve agent poisoning is principally respiratory: bronchorrhoea
    and bronchospasm, diaphragmatic and respiratory-muscle paralysis, and central
    apnoea converge to cause hypoxaemic respiratory failure.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "generalized signs of toxicity including status epilepticus, defecation, miosis, bronchospasm, bronchorrhea, paralysis and respiratory failure"
    explanation: Respiratory failure is a terminal manifestation of nerve agent poisoning.
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Most deaths are due to respiratory failure."
    explanation: Respiratory failure is the leading cause of death.
- name: Memory impairment
  category: Nervous System
  description: >-
    Long-term cognitive sequela documented years after acute exposure.
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Years after exposure to sarin, victims of the Tokyo subway attack presented with significant declines in psychomotor and memory functions"
    explanation: Tokyo subway sarin survivors showed long-term declines in memory function.
- name: Anxiety
  category: Nervous System
  description: >-
    Persistent anxiety and fear reported in survivors; consistent with
    amygdala-predominant seizure-driven neuropathology.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:21783510
    reference_title: "Acute and chronic effects of sarin exposure from the Tokyo subway incident."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "of 303 respondents, 45% still had some symptoms including eye problems, easy fatigability, headache, and fear."
    explanation: Persistent fear among one-year survivors supports lasting anxiety; graded indirect as fear is the quoted term.
biochemical:
- name: Blood cholinesterase activity
  presence: DECREASED
  notes: >-
    Reduced blood (plasma/erythrocyte) cholinesterase activity is the biochemical
    signature of nerve agent exposure. It is the assay used both to diagnose the
    disease and to monitor treatment: depression tracks acute severity, the value
    recovers with treatment and time, and the cholinesterase status guides oxime
    therapy.
  evidence:
  - reference: PMID:21783510
    reference_title: "Acute and chronic effects of sarin exposure from the Tokyo subway incident."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Reduction in plasma cholinesterase (ChE) activity was generally associated with the severity of acute signs of toxicity."
    explanation: In Tokyo subway sarin victims, lower plasma cholinesterase activity tracked with greater acute toxicity severity.
  - reference: PMID:21783510
    reference_title: "Acute and chronic effects of sarin exposure from the Tokyo subway incident."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "With time and treatment, the value rose quickly."
    explanation: Cholinesterase activity recovers with treatment and time, supporting its use for monitoring.
  - reference: PMID:32198755
    reference_title: "Diagnostics and treatment of nerve agent poisoning-current status and future developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources."
    explanation: Cholinesterase status guides oxime therapy duration and success.
environmental:
- name: Nerve agent vapour or liquid exposure
  exposure_term:
    preferred_term: exposure to organophosphorus compound
    term:
      id: ECTO:9000284
      label: exposure to organophosphorus compound
  description: >-
    Nerve agents are released deliberately as vapour or liquid in warfare,
    terrorism and targeted assassination; exposure is by inhalation and
    percutaneous absorption.
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "These compounds quickly and efficiently penetrate the human body via the skin, inhalation, and through the bloodstream."
    explanation: Establishes the dermal and inhalational routes of nerve agent exposure.
  - reference: PMID:32198755
    reference_title: "Diagnostics and treatment of nerve agent poisoning-current status and future developments."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment."
    explanation: Documents real-world warfare, assassination and terrorism exposure incidents.
  influences_mechanisms:
  - target: Acetylcholinesterase Inhibition
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Absorbed nerve agent reaches synaptic acetylcholinesterase and inhibits it.
    evidence:
    - reference: PMID:30159887
      reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: "Nerve agents selectively target and irreversibly inhibit acetylcholinesterase (AChE)"
      explanation: Absorbed nerve agent inhibits acetylcholinesterase, initiating the toxidrome.
prevalence:
- population: Incident-based (chemical-warfare and terrorism events)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Occurrence is incident-based rather than endemic, so no population rate is
    defensible. The 1995 Tokyo subway sarin attack brought 640 patients to a
    single hospital on the day of the attack; other mass-exposure events include
    Matsumoto (1994), Halabja (1988) and Ghouta/Syria (2013).
  evidence:
  - reference: PMID:21783510
    reference_title: "Acute and chronic effects of sarin exposure from the Tokyo subway incident."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "The St. Luke's International Hospital received 640 patients on the day of the attack."
    explanation: Documents the incident-based case count from the Tokyo subway sarin attack.
progression:
- phase: Acute cholinergic crisis
  age_range: Minutes to hours after exposure
  notes: >-
    Onset is within seconds to minutes after vapour exposure and can be delayed
    after dermal exposure. The cholinergic crisis (muscarinic, nicotinic and
    central overstimulation) evolves rapidly, and death in this phase is
    principally from respiratory failure. Surviving the first minutes of a vapour
    attack strongly predicts survival.
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "If victims can survive the first 15 to 20 min of a vapor attack, they will likely live."
    explanation: Characterises the tempo and survivability of the acute phase.
- phase: Long-term neuropsychiatric sequelae
  age_range: Months to years after exposure
  notes: >-
    Survivors, particularly after status epilepticus, can be left with persistent
    neurologic, cognitive and behavioural deficits and structural brain changes.
    One year after the Tokyo subway attack, 45% of responding survivors still
    reported symptoms.
  evidence:
  - reference: PMID:21783510
    reference_title: "Acute and chronic effects of sarin exposure from the Tokyo subway incident."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "of 303 respondents, 45% still had some symptoms including eye problems, easy fatigability, headache, and fear."
    explanation: Documents persistent symptoms one year after acute sarin exposure.
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Recent studies document long-term neurologic and behavior deficits, and technological advances demonstrate structural brain changes on magnetic resonance imaging."
    explanation: Documents long-term neurologic/behavioural deficits and structural brain changes.
treatments:
- name: Atropine
  description: >-
    Competitive muscarinic antagonist that reverses the muscarinic
    (secretory/bronchospastic) effects; titrated to drying of secretions.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atropine
      term:
        id: CHEBI:16684
        label: atropine
  target_mechanisms:
  - target: Muscarinic Receptor Overstimulation
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Standard-of-care treatment for OP nerve agent acute exposure includes atropine, a muscarinic antagonist, pralidoxime (2-PAM), an oxime that regenerates acetycholinesterase activity in those molecules that are not aged, and diazepam, a benzodiazepine to stop/attenuate seizures."
    explanation: Atropine is the standard-of-care muscarinic antagonist for nerve agent poisoning.
- name: Oxime reactivator (pralidoxime)
  description: >-
    Reactivates inhibited acetylcholinesterase by displacing the nerve agent
    from the catalytic serine; effective only in enzyme molecules that have not
    yet aged.
  therapeutic_modality: SMALL_MOLECULE
  notes: >-
    The therapeutic window closes as the inhibited enzyme ages at an
    agent-specific rate; once aging is complete, oxime reactivation is
    ineffective.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pralidoxime
      term:
        id: CHEBI:8354
        label: pralidoxime
  target_mechanisms:
  - target: Acetylcholinesterase Inhibition
  evidence:
  - reference: PMID:18555982
    reference_title: "Comparison of oxime reactivation and aging of nerve agent-inhibited monkey and human acetylcholinesterases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited acetylcholinesterase (AChE)"
    explanation: Oxime benefit depends on reactivating inhibited AChE, the mechanism this treatment targets.
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "pralidoxime (2-PAM), an oxime that regenerates acetycholinesterase activity in those molecules that are not aged"
    explanation: Pralidoxime regenerates AChE but only before the adduct ages.
- name: Benzodiazepine
  description: >-
    First-line anticonvulsant for nerve-agent seizures and status epilepticus;
    by stopping seizures it also limits the glutamatergic excitotoxicity that
    drives neuropathology. Efficacy declines the longer administration is delayed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
  target_mechanisms:
  - target: Central Cholinergic Overstimulation
  - target: Glutamatergic Excitotoxicity
  evidence:
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Anticonvulsants such as benzodiazepines decrease seizure activity and improve outcome, but their efficacy depends upon the administration time after exposure to the nerve agent."
    explanation: Benzodiazepines control nerve-agent seizures, with time-dependent efficacy.
- name: Decontamination and supportive care
  description: >-
    Removal from source, skin/clothing and ocular decontamination, airway
    management and mechanical ventilation.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Respiratory failure
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Treatment includes early airway and ventilatory support as well as antidotal therapy with atropine, pralidoxime, and diazepam."
    explanation: Airway and ventilatory support underpin management of respiratory failure.
  - reference: PMID:15979676
    reference_title: "The Tokyo subway sarin attack--lessons learned."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Preparation for a large-scale chemical attack by terrorists requires the prior establishment of a detailed decontamination plan"
    explanation: Decontamination planning is a core response to mass nerve agent exposure.
differential_diagnoses:
- name: Organophosphate (pesticide) poisoning
  disease_term:
    preferred_term: organophosphate poisoning
    term:
      id: MONDO:0800386
      label: organophosphate poisoning
  distinguishing_features:
  - >-
    Both are organophosphorus poisonings acting by acetylcholinesterase
    inhibition and share the cholinergic toxidrome, so they are not distinguished
    by a different mechanism. What separates them is pharmacodynamic: nerve agents
    are military-grade compounds of far greater potency, and their inhibited
    enzyme can age to an oxime-refractory state that collapses the therapeutic
    window for reactivators. The sibling entry Organophosphate_Poisoning models
    insecticidal organophosphorus poisoning, which already represents nerve-agent
    exposure as one environmental route into the same pathway; whether these
    should remain separate Disease entries, become a has_subtypes stratum, or be
    joined by a covering Grouping is a scope decision for a maintainer.
  evidence:
  - reference: PMID:16168308
    reference_title: "Organic phosphorus compounds--nerve agents."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "The organic phosphorous compounds (OPC) include both the military grade nerve agents and the organic phosphorous pesticides."
    explanation: Nerve agents and organophosphate pesticides are the two members of the same organophosphorus class, differing as military-grade versus agricultural agents.
  - reference: PMID:30159887
    reference_title: "Acute and long-term consequences of exposure to organophosphate nerve agents in humans."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Nerve agents are organophosphate (OP) compounds and among the most powerful poisons known to man."
    explanation: Supports the far greater potency of nerve agents relative to agricultural organophosphates.
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Oximes like pralidoxime salvage acetylcholine esterase by \"prying off\" NA, provided the attachment has not \"aged\" to an irreversible bond."
    explanation: Supports the aging-dependent collapse of the oxime window as the pharmacodynamic distinction.
datasets:

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References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Nerve Agent Poisoning · 2026-10-03T03:13:18Z · View source

Created Nerve Agent Poisoning (MONDO:0100331) as an acquired organophosphorus chemical-warfare toxidrome, a MONDO sibling of organophosphate (pesticide) poisoning. Pathophysiology modeled as a causal chain: nerve agent exposure -> acetylcholinesterase inhibition -> (branch: aging of the AChE adduct, oxime-refractory) -> synaptic acetylcholine accumulation -> muscarinic / nicotinic / central cholinergic overstimulation -> convergent respiratory failure; receptor-overstimulation nodes wired to 9 HP-coded phenotypes (all causally connected). Treatments: atropine (CHEBI:16684), pralidoxime oxime (CHEBI:8354), diazepam benzodiazepine (CHEBI:49575), decontamination/supportive care. Environmental exposure bound to ECTO:9000284 and linked TRIGGERS to AChE inhibition. Differential vs organophosphate pesticide poisoning (MONDO:0800386). Deep research requested as falcon but fell back to claude_code (no EDISON_API_KEY); report used as a lead only. Evidence anchored on PubMed reviews/clinical series: PMID:30159887 (Epilepsia human review, full text), PMID:16168308 (Crit Care Clin review), PMID:21783510 and PMID:15979676 (Tokyo subway sarin), PMID:18555982 (in-vitro aging/oxime kinetics), PMID:32198755 (treatment/exposure review). All 34 snippets exact-quote verified; validate-disorders, validate-terms, entity-refs, causal-targets, duplicate-keys, enum-values, coarse-phenotypes, snippet-grading, environmental-evidence all pass. No GeneReviews chapter (acquired toxidrome). Bradycardia was considered but omitted for lack of a quotable source.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5-5 8 citations 2026-10-03T02:54:51.320737

1. Disease Information

Overview. Nerve agent poisoning is acute cholinergic toxicity from organophosphorus nerve agents. These are the G-series (tabun, sarin, soman, cyclosarin), VX and the V-series, and the "Novichok" (A-series) agents. They irreversibly inhibit acetylcholinesterase (AChE). Acetylcholine then accumulates at muscarinic and nicotinic synapses and in the CNS. [background, unsourced]
Treatment summary. Therapy has three components: atropine, a benzodiazepine and an oxime (Merck Manual; Dawson, AMMA J 2023).
Identifiers and synonyms. I did not check ICD-10, ICD-11, MeSH or OMIM codes. Likely ICD-10 candidates are T59.8 or T60.x (organophosphate toxic effect), which need checking. Synonyms: nerve gas poisoning, organophosphorus nerve agent intoxication, chemical warfare nerve agent toxicity.
Data source. Information comes from aggregated case series and incident reports: Tokyo 1995, Ghouta 2013, Salisbury 2018.
Scope note. This is an exposure-defined toxic disorder, not a Mendelian one. Check the dismech scope decisions (docs/explanation/design-decisions.md) on toxic exposures. The nearest precedents are Arsenic_Poisoning and Digitalis_Poisoning. Decide whether this is one entry or whether organophosphate pesticide poisoning should be lumped in. The mechanism is the same, but the agents' potency and aging kinetics differ.

2. Etiology

Cause. Exposure to an organophosphorus nerve agent by inhalation, dermal contact or ingestion. Settings are military or terrorist use, assassination, and accidents or industrial release. [background, unsourced]
Documented incidents
Tokyo, 1995. The sarin attack killed 13 and sickened more than 6,000 (see PLoS ONE 2020 follow-up).
Ghouta, Syria, 2013. Sarin rockets; the US estimate was 1,429 deaths including 426 children (per the Wikipedia summary, which is not a primary source).
Salisbury, UK, 2018. Novichok; the NHS response was described as its longest-running major incident, about 72 days (Frontiers in Toxicology review; PMC9905702).
Genetic risk and modifiers. Butyrylcholinesterase (BCHE) variants and paraoxonase 1 (PON1) polymorphisms plausibly modify susceptibility. I found no source for this in these searches; mark it as a literature gap. [background, unsourced]
Protective factors. Pyridostigmine pretreatment is used by the military against soman. Protective equipment and rapid decontamination also protect. [background, unsourced]
Gene-environment interaction. Not established from the sources retrieved.

3. Phenotypes

These are acute muscarinic, nicotinic and CNS features. Frequencies were not obtained.

Phenotype	Type	Suggested HPO term (name only; look up the ID)
Miosis (eye pain, blurred vision)	sign/symptom	Miosis
Rhinorrhea, salivation, bronchorrhea	sign	Excessive salivation; Rhinorrhea
Bronchoconstriction, dyspnea	sign/symptom	Dyspnea; Wheezing
Nausea, vomiting, diarrhea, incontinence	symptom	Nausea and vomiting; Diarrhea
Bradycardia	sign	Bradycardia
Fasciculations, weakness, paralysis	sign	Fasciculations; Muscle weakness
Seizures	sign	Seizure
Altered consciousness, headache	symptom	Confusion; Headache
Respiratory failure	sign	Respiratory failure

Salisbury Novichok. Reported features include nausea and vomiting, headache, altered mental state, blurred or painful vision, and involuntary faecal incontinence (Star summary of the NHS account; a secondary source, so prefer PMC9905702).
Onset and course. Onset is acute: seconds to minutes after vapor exposure, longer after dermal VX. Phenotypes are episodic and self-limited if the patient survives. [background, unsourced]
Chronic and psychiatric sequelae in Tokyo survivors
Somatic symptoms, especially eye symptoms, were present in 60–80% and had not decreased.
Posttraumatic stress response was present in 35.1% with no change over time.
This comes from annual questionnaires, 2000–2009, in a PLoS ONE 2020 study that described most acute symptoms as transient.
Evidence type: HUMAN_CLINICAL. The data are self-reported.

4. Genetic/Molecular Information

Causal genes. None. The cause is environmental.
Molecular target. ACHE (AChE) is the primary target. BCHE is a scavenger and biomarker. Candidate modifiers are BCHE and PON1 variants. All of this is [background, unsourced]. Use lowercase hgnc: CURIEs after lookup.
Epigenetic and chromosomal. Not applicable, and nothing was retrieved.

5. Environmental Information

Exposure agents. Sarin (GB), soman (GD), tabun (GA), cyclosarin (GF), VX and Novichok-class agents.
Routes. Inhalation (vapor or aerosol), dermal (especially VX) and ocular. Ingestion occurs in poisonings.
Binding. Look up ECTO exposure terms and CHEBI agent terms, and check that the term fits the specific agent. Per the project rules, run the ECTO search verbatim before writing any note that no term exists. Search both "anaesthetic"-style spelling variants and general terms such as "organophosphate" and "nerve agent".
Infectious agents and lifestyle factors. Not applicable.

6. Mechanism / Pathophysiology

Causal chain (steps 1–3 are mechanistic knowledge [background, unsourced]; aging is supported by StatPearls via search):

Nerve agent enters the body by inhalation, skin or eye and is absorbed systemically. This leads to
phosphylation of the active-site serine of AChE, which inactivates the enzyme. This results in
accumulation of acetylcholine at cholinergic synapses and neuromuscular junctions. This causes
over-stimulation of muscarinic receptors (parasympathetic effector organs and glands), nicotinic receptors (autonomic ganglia and the neuromuscular junction), and central cholinergic circuits. This leads to
the muscarinic toxidrome (miosis, secretions, bronchoconstriction, bradycardia, GI hypermotility), nicotinic effects (fasciculations, then depolarization-block paralysis) and CNS effects (seizures, coma). The respiratory consequences arise from several of these together: bronchorrhea, bronchospasm, respiratory-muscle paralysis and central apnea. These are the usual cause of death.
Branch (aging). The phosphylated enzyme loses an alkyl group and is "aged", which makes the inhibition permanent and oxime reactivation ineffective. The time to aging differs by agent: soman about 1–2 minutes, VX about 30 hours (search summary of StatPearls). Aging therefore sets the window for oxime therapy.
Branch (seizures). Sustained seizures can cause excitotoxic brain injury. This step is plausible but was not sourced here; mark it as inferred. [background, unsourced]

Suggested GO terms (look up IDs): acetylcholine catabolic process, cholinergic synaptic transmission, muscarinic acetylcholine receptor signaling pathway, regulation of muscle contraction. Suggested cell types: skeletal muscle fiber, neuron, smooth muscle cell, exocrine gland cell (look up CL terms). Omics and advanced technologies: nothing retrieved. Do not write placeholder content.

7. Anatomical Structures Affected

Primary systems. Nervous system (central and autonomic), neuromuscular junction, respiratory tract and lungs, eye (pupil, ciliary muscle), exocrine glands, GI tract, heart. Look up UBERON terms for each.
Subcellular site. The synaptic cleft and the AChE active site.
Lateralization. Bilateral and systemic. Dermal exposure can cause localized sweating and fasciculation at the contact site. [background, unsourced]

8. Temporal Development

Onset. Acute, from seconds to minutes after inhalation. Dermal onset is delayed (up to hours).
Course. Self-limited if the patient survives the acute phase. Recovery of enzyme activity depends on new AChE synthesis. Some survivors have persistent symptoms: Tokyo survivors reported chronic eye and psychological symptoms for 10+ years (PLoS ONE 2020).
Critical period. The oxime window is set by aging time (see section 6). Seizures need prompt control.

9. Inheritance and Population

Inheritance. Not applicable.
Epidemiology. Occurrence is incident-based.
Tokyo 1995: 13 deaths and over 6,000 sickened (PLoS ONE 2020).
Ghouta 2013: US estimate of 1,429 deaths (Wikipedia, secondary).
A population rate cannot be given. Per the prevalence rules, prevalence_class: NOT_YET_DOCUMENTED or CASES_IN_LITERATURE is more appropriate than a made-up rate.
Demographics. Civilians, military personnel and first responders. Children are affected, as in Ghouta. No sex-ratio data were retrieved.

10. Diagnostics

Not covered by the sources retrieved. Standard content, [background, unsourced]: - Diagnosis is clinical, based on the cholinergic toxidrome, and treatment should not wait for lab confirmation. - Red blood cell AChE and plasma BChE activity are supportive tests. Agent-specific adducts or metabolites (for example, BChE adducts, urinary alkyl methylphosphonates) are used in forensic confirmation. - Differential diagnosis includes organophosphate or carbamate pesticide poisoning, other toxidromes and seizure disorders. - There are no genetic or screening tests.

Find sources for these before curating them.

11. Outcome/Prognosis

Mortality. Highly variable by agent, dose and access to treatment. Tokyo had a low fatality rate relative to casualties (13 of more than 6,000). No Ghouta mortality figure beyond the estimate above was retrieved.
Long-term. Persistent somatic and psychological symptoms in Tokyo survivors (above).
Prognostic factors: time to treatment and the agent's aging rate. [background, unsourced]

12. Treatment

All sourced to the search summaries of Merck Manual, Dawson 2023 and StatPearls:

Atropine. A competitive muscarinic antagonist that treats symptoms but does not affect the agent. The summaries give 2 mg IV every 5–10 minutes, with doses doubled if there is no improvement.
Oximes. Nucleophiles that remove the phosphoryl group from AChE. Examples: pralidoxime (2-PAM), HI-6, obidoxime and MMB-4. They are ineffective once the enzyme has aged.
Benzodiazepines. For seizures; they are part of autoinjectors and treatment regimens.
Supportive care. Decontamination, airway management and ventilation. [background, unsourced]
Suggested NCIT treatment terms. Pharmacotherapy NCIT:C15986 and Supportive Care NCIT:C15747 are from the project's CLAUDE.md list. Use therapeutic_agent for each drug (CHEBI), with therapeutic_modality: SMALL_MOLECULE.
Experimental therapy and trials. Not searched. The Dawson 2023 review is a lead for newer oximes and adjuncts.
Pharmacogenomics. Not retrieved.

13. Prevention

Primary prevention rests on arms control, protective equipment and decontamination. Military pyridostigmine pretreatment is mentioned in section 2. [background, unsourced]
Secondary and tertiary prevention include rapid antidote autoinjectors and psychological follow-up, given the PTSR figure above. No vaccines exist.
Genetic counseling does not apply.

14. Other Species / Natural Disease

Nothing was retrieved, and there is no natural disease. Animals are affected as experimental subjects or by environmental release. NCBI Taxon, breed and OMIA entries do not apply.

15. Model Organisms

No sources were retrieved on models. Animal models exist (rodents, guinea pigs, non-human primates), as do in vitro AChE assays. I did not research them. [background, unsourced]

Use animal_models: for whole-animal models, with evidence_source: MODEL_ORGANISM.
Guinea pigs are commonly preferred for medical countermeasure studies because they have low plasma carboxylesterase. This is a claim to verify.
Source animal-model and medical-countermeasure studies before adding entries.

Gaps Before Curation

Find and cache primary sources, with PMIDs, for the following:
clinical series (Tokyo and Ghouta clinical papers);
the Salisbury case reports;
the aging kinetics of each agent;
oxime efficacy;
seizure and neuroprotection data.
Verify MONDO, ECTO, CHEBI, HP, GO, CL and UBERON terms by lookup.
Check the scope decision on lumping with organophosphate pesticide poisoning.
Add diagnostics, animal-model and epidemiology evidence. Those sections are currently unsourced.

Sources Used

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	0
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	3
Resolved	3
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

Every term resolved, and every label the report gave matched.

Nerve Agent Poisoning

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Pathophysiology

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Phenotypes

Medical Actions

Environmental Factors

Biochemical Markers

Progression

Prevalence

Differential Diagnoses

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References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Gaps Before Curation

Sources Used

Reference Validation

Term Validation