🔗

Mappings

MONDO

MONDO:0043230 ciguatera fish poisoning

semapv:ManualMappingCuration

ICD-10-CM

ICD10CM:T61.0 Ciguatera fish poisoning

semapv:ManualMappingCuration

?

Discussions and Knowledge Gaps

2

Does variation in human voltage-gated sodium channel genes modify susceptibility to, or the symptom profile of, ciguatera fish poisoning?

KNOWLEDGE GAP OPEN cfp-host-nav-susceptibility

Attached to

pathophysiology#Voltage-Gated Sodium Channel Site 5 Activation

Ciguatoxin acts directly on Nav1.1 to Nav1.9, and the isoform carrying a given symptom has been separated pharmacologically in rodents, so allelic variation at SCN1A, SCN9A, SCN10A or SCN11A is a biologically obvious candidate modifier of who becomes symptomatic and how. No human genetic association study exists. This entry deliberately has no `genetic:` section rather than one inferred from channel pharmacology, and that absence is the gap being recorded.

Show evidence (1 reference)

PMID:28225079 SUPPORT Model Organism

"P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."

Establishes that different isoforms carry different symptoms, which is what makes host allelic variation a plausible modifier worth testing.

Every experimental model of ciguatera reproduces the acute channel lesion over minutes to hours. None reproduces the chronic relapsing syndrome that affects at least a fifth of patients for months to years. Does chronicity reflect persisting channel dysregulation, a sensitised nociceptive circuit, or something the acute models cannot express?

HUMAN MODEL MISMATCH OPEN cfp-chronic-phase-no-model

Attached to

progression#Chronic ciguatera pathophysiology#Repetitive Firing of Peripheral Sensory Afferents

The mismatch matters because it is the chronic phase, not the acute one, that carries most of the disability, and every mechanistic claim about it in the literature is inference from acute pharmacology. The rat cold hypersensitivity model and the mouse CGRP release preparations recorded in this entry both measure an effect within hours of toxin application; neither has been run over the time course on which human symptoms relapse, and the reported triggers of relapse - alcohol, nuts, a further fish meal - have no counterpart in any model. Reactivation months after the toxin has cleared is not obviously a channel-occupancy phenomenon at all, which is what makes this a translational gap rather than a missing experiment.

Show evidence (2 references)

PMID:34564650 SUPPORT Human Clinical

"Even though chronic CP cases are regularly reported, studies dedicated to the understanding of this phenomenon are scarce, especially due to the lack of a clear consensus regarding its clinical definition."

States that the chronic phase is under-studied, which is the human side of the mismatch.

PMID:34564650 SUPPORT Human Clinical

"Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"

Establishes that the unmodelled phase is the common one, not an edge case.

⚙

Pathophysiology

12

Gambierdiscus Ciguatoxin Production on Reef Substrate

The environmental origin of the toxin. Benthic dinoflagellates of the genera Gambierdiscus and Fukuyoa live epiphytically on macroalgae, dead coral and reef detritus in tropical and subtropical waters, where they synthesise the ciguatoxin precursors known as gambiertoxins. Toxin production is species-specific rather than a property of the genus as a whole, which is why Gambierdiscus abundance alone is a poor predictor of local risk.

Downstream

Trophic Biotransformation and Biomagnification in Reef Fish Algal gambiertoxins enter the reef food web when herbivorous fish graze the substrate the dinoflagellates colonise.

Show evidence (3 references)

PMID:41610130 SUPPORT Other

"Ciguatoxins (CTXs) are produced by marine microbial eukaryotes (Gambierdiscus/Fukuyoa, Dinophyta: Alveolata) that live epiphytically on macroalgae and other substrates."

Establishes the producing organisms and the substrate they occupy.

PMID:41610130 SUPPORT Other

"Of newly isolated Gambierdiscus strains, only the three G. polynesiensis produced P-CTXs."

Supports the species-specificity point in this description - most isolates from an endemic site made no Pacific ciguatoxin at all.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"These toxins originate from benthic microalgae of the genus Gambierdiscus and Fukuyoa"

Independent statement of the algal origin of the toxins.

Trophic Biotransformation and Biomagnification in Reef Fish

Gambiertoxins taken up by herbivorous fish are oxidised by fish hepatic cytochrome P450 enzymes into more polar and substantially more potent ciguatoxin congeners, and accumulate as those fish are eaten by carnivorous predators. The end products differ by ocean basin - P-CTX-1 in the Pacific, C-CTX-1/2 in the Caribbean, I-CTX in the Indian Ocean - and the Pacific end product is the most toxic congener known for mammals.

Downstream

Ingestion and Systemic Distribution of Ciguatoxin The concentrated toxin burden in predatory reef fish flesh is what a human meal delivers.

Show evidence (3 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"During this transfer, GTXs are not only accumulated within the marine food chain but also biotransformed to become more polar and more toxic CTXs"

States both halves of this node - accumulation and toxifying biotransformation.

PMID:37044143 SUPPORT In Vitro

"Metabolism in vitro by fish liver microsomes converted algal C-CTX5 into C-CTX1/2, the dominant CTX in ciguatoxic fish from the Caribbean."

Direct demonstration that fish hepatic metabolism performs the algal-precursor to fish-congener conversion this node asserts.

PMID:28867800 SUPPORT BACKGROUND Other

"The precursors are oxidized to CTXs in the fish liver by cytochrome enzymes to become the most potent mammalian voltage-gated sodium channel (VGSC) toxins known."

Names the enzymatic route and the resulting increase in mammalian potency.

Ingestion and Systemic Distribution of Ciguatoxin

The exposure event. A human meal of contaminated reef fish delivers ciguatoxin that cannot be detected by taste, smell or appearance and is not destroyed by cooking, salting or freezing. Because the toxins are lipophilic they are readily absorbed and slowly eliminated, and distribute to excitable tissue throughout the body.

Animal models

Cook Islands naturally occurring canine and feline ciguatera Dog partially recapitulates The same exposure route and the same toxin, in a naturally exposed non-human population with veterinary follow-up that human series rarely match.

Downstream

Voltage-Gated Sodium Channel Site 5 Activation Absorbed ciguatoxin reaches voltage-gated sodium channels in peripheral nerve, enteric and autonomic neurons, and cardiac tissue.

Potassium Current Inhibition in Sensory Neurons The same absorbed toxin independently reaches potassium conductances in dorsal root ganglion neurons. This is a parallel branch of the exposure, not a consequence of the sodium lesion: ciguatoxin acting on one channel class does not cause its action on the other, and the two converge downstream at afferent firing rather than one feeding the other.

Show evidence (3 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs)."

Establishes fish consumption as the causal exposure for the disease.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"CTXs are thermo- and relatively acid- and basic-stable toxins that are unaffected by cooking, salting or congealing"

Supports the claim that ordinary preparation does not remove the exposure.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"lipid-soluble and therefore readily absorbed and slowly eliminated in fish and humans"

Source of the absorption and elimination claim in this description.

Voltage-Gated Sodium Channel Site 5 Activation

Ciguatoxins bind neurotoxin receptor site 5 on the alpha subunit of voltage-gated sodium channels - the same site targeted by the structurally related brevetoxins - and act as allosteric activators rather than blockers. Binding shifts the voltage dependence of activation to more hyperpolarised potentials and impairs inactivation, so a fraction of channels is open at or near the resting membrane potential. The effect is close to non-selective across Nav1.1 to Nav1.9, with the largest activation shifts at the tetrodotoxin-resistant isoforms Nav1.8 and Nav1.9.

ciguatoxin-activated voltage-gated sodium channel activity GO:0005248 ⇑ GAIN OF FUNCTION

Downstream

Sustained Sodium Influx and Membrane Depolarization Channels opening at resting potential admit sodium continuously rather than only during an action potential.

Show evidence (4 references)

PMID:28225079 SUPPORT BACKGROUND Other

"This diverse symptomatology is believed to be caused by the interaction of the ciguatoxins with site 5 of the voltage-gated sodium channels (NaV)"

Names site 5 as the molecular target. Graded OTHER because the quoted sentence reports a mechanistic belief about a binding site and describes no study of its own; the direct patch-clamp measurement below is the real support for this node.

PMID:28225079 SUPPORT In Vitro

"P-CTX-1 significantly shifted the V1/2 for the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes"

Direct patch-clamp measurement of the activation shift, across every human Nav isoform tested.

PMID:33066435 SUPPORT REVIEW SYNTHESIS In Vitro

"Alterations of TTX-s Nav properties comprise a shift of the activation threshold voltage to more negative values associated with an impairment of their inactivation process"

States the second half of the biophysical claim, impaired inactivation.

+ 1 more reference

Potassium Current Inhibition in Sensory Neurons

Ciguatoxins also inhibit delayed-rectifier and A-type potassium currents in dorsal root ganglion neurons. Because these currents normally repolarise the membrane and damp repetitive discharge, their loss amplifies the excitability produced by the sodium-channel effect rather than acting independently of it.

dorsal root ganglion sensory neuron CL:1001451

delayed rectifier potassium channel activity GO:0005251 ↓ DECREASED A-type potassium channel activity GO:0005250 ↓ DECREASED

Downstream

Repetitive Firing of Peripheral Sensory Afferents Loss of the repolarising currents that would otherwise terminate a burst.

Show evidence (2 references)

PMID:26454262 SUPPORT BACKGROUND In Vitro

"Ciguatoxins also inhibit delayed rectifier and A-type potassium currents in dorsal root ganglia neurones, resulting in further increases in neuronal excitability"

States both the potassium-current effect and its amplifying role.

PMID:28535116 SUPPORT REVIEW SYNTHESIS In Vitro

"In vitro experiments of isolated neurons demonstrate that ciguatoxins produce neuronal edema, open certain sodium channels, block potassium channels, cause uncontrolled and repetitive action potentials after a stimulus."

Independent synthesis naming potassium-channel block alongside the sodium effect and the repetitive firing it produces.

Sustained Sodium Influx and Membrane Depolarization

Continuous sodium entry through toxin-modified channels depolarises excitable cells, raises intracellular calcium, and imposes an osmotic load that water follows. This is the single cellular lesion from which the neurological, gastrointestinal and cardiovascular branches of the syndrome all descend.

sodium ion transmembrane transport GO:0035725 ↑ INCREASED membrane depolarization GO:0051899 ↑ INCREASED

Downstream

Repetitive Firing of Peripheral Sensory Afferents A depolarised afferent fires without a stimulus and keeps firing after one.

Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents Depolarisation, not firing, is what shifts the voltage dependence of TRPA1 activation so that cooling opens it. Cold sensitisation is therefore a sibling consequence of the same depolarisation as the repetitive firing, not a consequence of the firing itself.

Nodal and Adaxonal Schwann Cell Swelling Sodium entry with obligate water movement is the osmotic driver of the swelling.

Enteric and Autonomic Neuron Hyperexcitability

Cardiac Conduction and Vasomotor Disturbance

Show evidence (1 reference)

PMID:26454262 SUPPORT BACKGROUND In Vitro

"likely leading to channel activation at resting membrane potentials, ongoing activity in primary sensory afferent fibres, axonal swelling and elevation of intracellular calcium"

Names the depolarisation, the calcium rise and the swelling that define this node.

Repetitive Firing of Peripheral Sensory Afferents

Depolarised primary afferents discharge spontaneously and repetitively, and respond excessively to stimuli that would normally be innocuous. Which isoform carries which symptom has been separated pharmacologically: Nav1.8 block significantly decreases visceral pain behaviour while block of the tetrodotoxin-sensitive Nav1.7 and Nav1.6 significantly decreases cutaneous pain behaviour. Neither block abolishes it.

peripheral sensory afferent neuron CL:3000004

action potential GO:0001508 ↑ INCREASED

Downstream

Calcium-Dependent CGRP Release and Neurogenic Inflammation

Perioral and distal paresthesia

Hyperesthesia

Myalgia

Arthralgia Joint pain travels with the myalgia in every series, but no source traces it to afferent hyperexcitability specifically, so the intermediates are recorded as unknown rather than guessed.

Muscle weakness Motor complaints are common, and depolarisation to the point of inexcitability is the obvious candidate route, but no cited source demonstrates it in ciguatera.

Fatigue Asthenia acutely and tenacious fatigue chronically. The route from peripheral afferent hyperexcitability to fatigue is not established; the edge records that the phenotype belongs to this branch of the syndrome, not that the mechanism is known.

Headache

Ataxia Sensory ataxia from disturbed afferent input is the plausible route, but no source cited here distinguishes it from a cerebellar or vestibular one.

Hyporeflexia

Dysuria

Parageusia

Show evidence (2 references)

PMID:28225079 SUPPORT Model Organism

"The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation,..."

Single-fibre recordings establishing afferent hyperexcitability as the cellular lesion.

PMID:28225079 SUPPORT Model Organism

"P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."

Supports the isoform-to-symptom mapping this description states.

Nodal and Adaxonal Schwann Cell Swelling

Sodium entry with obligate water movement swells the nodes of Ranvier of myelinated fibres and the adaxonal Schwann cell cytoplasm. This is the one structural lesion of ciguatera that has been seen in patients: sural nerve biopsies in severe cases show adaxonal Schwann cell oedema with axonal compression and vesicular myelin degeneration, and skin biopsy months after poisoning has shown diffuse axonal swellings with preserved intraepidermal fibre density.

myelinating Schwann cell CL:0000218

Downstream

Perioral and distal paresthesia Structural disturbance at the node accompanies the abnormal sensation, although the quantitative contribution of swelling relative to ectopic firing has not been separated in patients.

Show evidence (2 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"This was confirmed by a biopsy of the sural nerve, which revealed a striking edema in the adaxonal layer of the Schwann cell cytoplasm, with axonal compression and vesicular degeneration of the myelin."

Human tissue evidence for the adaxonal Schwann cell oedema this node asserts.

PMID:33066435 SUPPORT REVIEW SYNTHESIS In Vitro

"Motor nerve terminals and perisynaptic Schwann cell soma of frog neuromuscular junctions (NMJs) exposed to CTXs were also swollen"

Analogous swelling in a directly exposed preparation, where the human biopsies are observational. Note this is the perisynaptic Schwann cell at the neuromuscular junction, a different cell population from the adaxonal myelinating Schwann cell this node is about.

Calcium-Dependent CGRP Release and Neurogenic Inflammation

Depolarised sensory terminals release calcitonin gene-related peptide in a manner dependent on extracellular sodium and calcium and independent of thermosensory transient receptor potential channel activation. Nav1.9 alone, and Nav1.7 with Nav1.1 together, carry most of the release. Intradermal ciguatoxin in human volunteers produces a long-lasting painful axon reflex flare, which is the neurogenic-inflammation readout of this step, and CGRP signalling is the plausible route from afferent firing to itch.

peptidergic CGRP-expressing sensory neuron CL:4033176

CGRP release from sensory nerve terminals GO:0007269 ↑ INCREASED

Downstream

Hyperhidrosis Sweating follows the cutaneous axon reflex rather than the enteric branch: intracutaneous ciguatoxin in human volunteers elicits axon reflex sweating through efferent cholinergic sympathetic skin nerves.

Pruritus CGRP-dependent neurogenic signalling is the proposed route to the itch that is one of the three characteristic sensory signs.

Show evidence (2 references)

PMID:28867800 SUPPORT Model Organism

"P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels."

Establishes the ionic dependence of the release, which is what makes it downstream of the channel lesion.

PMID:28867800 SUPPORT BACKGROUND Human Clinical

"local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals"

The human experimental result behind the axon reflex flare in this description, and the only human experimental observation in this entry. Graded HUMAN_CLINICAL because the quoted work was done in human subjects, with quote_role BACKGROUND because this paper is reporting its own earlier study rather than the experiment it goes on to describe.

Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents

Ciguatoxin confers cold sensitivity on a subpopulation of normally cold-insensitive afferents that co-express Nav1.8 and TRPA1, so innocuous cooling drives a nociceptive response. In spinal recordings, cold hypersensitivity is abolished by a Nav1.8 antagonist, only partially prevented by a TRPA1 antagonist, and unaffected by a TRPM8 antagonist - which places the lesion on the Nav1.8/TRPA1 population rather than on the canonical cold receptor.

Nav1.8/TRPA1-positive primary afferent neuron CL:0000101

detection of temperature stimulus involved in sensory perception of pain GO:0050965 ⚠ ABNORMAL

Animal models

Rat spinal dorsal horn ciguatoxin cold hypersensitivity model Rat recapitulates Local ciguatoxin reproduces the cold hypersensitivity, and the channel dependence is established by selective antagonists.

Downstream

Cold allodynia

Show evidence (2 references)

PMID:26454262 SUPPORT Model Organism

"Subcutaneous injection of 10 nm ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling."

The primary measurement - cooling responses increase after local ciguatoxin.

PMID:26454262 SUPPORT Model Organism

"Both mechanical and cold hypersensitivity were completely prevented by co-injection with the Nav 1.8 antagonist A803467, whereas the transient receptor potential ankyrin 1 (TRPA1) antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to..."

The pharmacological dissection that assigns the effect to Nav1.8 and TRPA1.

Enteric and Autonomic Neuron Hyperexcitability

Sodium channel activation in enteric and autonomic neurons produces the earliest and most consistent phase of the illness - nausea, vomiting, watery diarrhoea and abdominal cramping beginning within hours of the meal - together with autonomic signs such as profuse sweating and hypersalivation. This phase is self-limited over one to a few days while the neurological phase continues.

enteric neuron CL:0007011

action potential GO:0001508 ↑ INCREASED

Downstream

Nausea

Vomiting

Diarrhea

Abdominal pain

Show evidence (3 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal disorders include nausea, vomiting, abdominal pain and diarrhea (watery stools)."

Names the gastrointestinal features this node produces.

PMID:28225079 SUPPORT Model Organism

"P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."

Ties the visceral pain component specifically to sodium channel activation. It covers abdominal pain only; the emetic, secretory and autonomic claims in this node rest on the enteric-plexus evidence below and on the clinical description above.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Model Organism

"In mice experimentally intoxicated with a single dose of CTX, non-myelinated nerves of the enteric nervous system (the myenteric Auerbach plexus and submucosal Meissner plexus) were swollen, as were synapses in the myenteric plexus and vas deferens smooth muscle layers."

Direct evidence that the enteric nervous system is a substrate of the toxin, which is the mechanistic claim this node makes and the one the symptom lists above do not establish.

Cardiac Conduction and Vasomotor Disturbance

How ciguatoxin slows the heart is contested, and both positions are recorded below. The clinical literature argues an indirect route: stimulation of unmyelinated vagal cardiac afferents inhibiting central vasomotor centres, so sympathetic output and peripheral resistance fall. Mouse histology argues a direct one: cardiac myocytes swell in a pattern read as myocardial sodium channel activation rather than as an action on cardiac autonomic nerves. Either route, combined with hypovolaemia from gastrointestinal losses, produces bradycardia, hypotension and conduction disorders. These are the least frequent features but the ones that make the illness life-threatening. They do respond to atropine, fluids and dopamine, but reversal can require unusually large or prolonged atropine dosing - 45 mg and 30 mg over 48 hours in the two published cases cited here.

cardiac muscle cell CL:0000746

membrane depolarization GO:0051899 ↑ INCREASED

Downstream

Bradycardia

Hypotension

Show evidence (6 references)

PMID:22574244 SUPPORT Human Clinical

"We report two patients with persistent bradycardia and hypotension after eating mackerel fish."

Direct clinical observation of the cardiovascular phenotype this node produces.

PMID:25333356 SUPPORT Human Clinical

"Bradycardia and hypotension, which can be life-threatening, are common."

Supports the severity claim in this description from a territory-wide case series.

PMID:22574244 SUPPORT Human Clinical

"ciguatoxin stimulates the unmyelinated afferent cardiac branches of the vagus nerve which leads to a tonic inhibition of central vasomotor centers with reduced sympathetic output and peripheral vascular resistance, causing bradycardia, continued hypotension, and peripheral vasodilatation."

Spells out the vagal-afferent and central-vasomotor route this node records.

+ 3 more references

✶

Histopathology

2

Adaxonal Schwann cell oedema with axonal compression on sural nerve biopsy

The one structural lesion of ciguatera documented in human tissue. Sural nerve biopsy in severe cases shows striking oedema of the adaxonal layer of the Schwann cell cytoplasm, compressing the axon, with vesicular degeneration of the myelin.

Show evidence (2 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"This was confirmed by a biopsy of the sural nerve, which revealed a striking edema in the adaxonal layer of the Schwann cell cytoplasm, with axonal compression and vesicular degeneration of the myelin."

Describes the finding exactly as recorded here.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"In two severe cases, edema of myelin fibers, sometimes intra-axonal, or of the adaxonal Schwann cell cytoplasm, were revealed in biopsied sural nerves"

Establishes how few cases this rests on - two - which is why it is recorded as a finding rather than as a diagnostic criterion.

Diffuse axonal swellings with preserved intraepidermal nerve fibre density on skin biopsy

Skin biopsy of the distal leg two months after intoxication shows diffuse axonal swellings while the density of intraepidermal nerve fibres remains normal. The combination matters: it argues that the persisting sensory disturbance is a functional and structural change in surviving fibres rather than a small-fibre neuropathy with fibre loss.

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"A skin biopsy from the distal leg, carried out 2 months after intoxication, revealed that the density of the intraepidermal nerve fibers was normal, but diffuse axonal swellings were observed"

States both halves of the finding - swelling present, fibre density preserved - which is the whole of the inference drawn here.

⬡

Pathograph

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

●

Phenotypes

21

Cardiovascular 2

Bradycardia FREQUENT HP:0001662

Show evidence (2 references)

PMID:22574244 SUPPORT Human Clinical

"Although cardiovascular symptoms are rare with ciguatoxin, we report two cases with bradycardia and hypotension."

Direct case documentation of the sign, and of its relative rarity.

PMID:36006197 SUPPORT Human Clinical

"cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders)"

Source of the 22% figure quoted in this description.

Hypotension FREQUENT HP:0002615

Show evidence (2 references)

PMID:25333356 SUPPORT Human Clinical

"Bradycardia and hypotension, which can be life-threatening, are common."

Establishes hypotension as a recognised and potentially fatal feature, and as common - the basis for the FREQUENT grading.

PMID:29449664 SUPPORT Human Clinical

"93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."

Puts a number on the cardiovascular syndrome this phenotype belongs to.

Digestive 3

Nausea VERY_FREQUENT HP:0002018

Temporal: ACUTE

Show evidence (1 reference)

PMID:36006197 SUPPORT Human Clinical

"Acute features consisted in general (91%; mainly, myalgia pruritus, and asthenia), gastrointestinal (90%; mainly diarrhea, abdominal pain, and nausea), neurological (72%; mainly, paresthesia, dysgeusia, and impairment of hot/cold feeling), and cardiovascular manifestations (22%; bradycardia,..."

Names nausea among the dominant gastrointestinal features, present in 90% of a 149-patient series.

Vomiting VERY_FREQUENT HP:0002013

Temporal: ACUTE

Show evidence (2 references)

PMID:34564650 SUPPORT Human Clinical

"Gastrointestinal manifestations (i.e., diarrhea, vomiting, nausea, and abdominal pain) usually occur first, sometimes accompanied by cardiovascular disorders, mostly bradycardia and hypotension."

Names vomiting among the first-appearing gastrointestinal manifestations.

PMID:29449664 SUPPORT Human Clinical

"93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."

Source of the VERY_FREQUENT grading: the gastrointestinal syndrome this phenotype belongs to was present in 93.9% of 234 cases.

Diarrhea VERY_FREQUENT HP:0002014

Temporal: ACUTE

Show evidence (2 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal disorders include nausea, vomiting, abdominal pain and diarrhea (watery stools)."

Names watery diarrhoea specifically.

PMID:29449664 SUPPORT Human Clinical

"93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."

Source of the VERY_FREQUENT grading: the gastrointestinal syndrome this phenotype belongs to was present in 93.9% of 234 cases.

Ear 1

Vertigo HP:0002321

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."

Names vertigo first among these neurological signs.

Genitourinary 1

Dysuria HP:0100518

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"dental pain, headaches, painful micturition and other urogenital pain"

Names painful micturition among the sensory disturbances. The same sentence names dental pain, which is not added as a phenotype because HPO has no tooth-pain term - a label search returns only `HP:0005216` Impaired mastication, which denotes something else.

Head and Neck 1

Parageusia HP:0031249

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Myalgia, especially in the muscles of the legs, is also frequently reported, as well as other sensory disorders, including a metallic taste"

Names metallic taste among the reported sensory disorders.

Integument 2

Pruritus VERY_FREQUENT HP:0000989

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Pruritus (itch), which is a very common symptom, begins 1 to 2 days after the ciguateric meal, sometimes associated with a skin rash."

States the frequency, the latency and the rash association recorded here.

Hyperhidrosis HP:0000975

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Autonomic signs, including profuse sweating or hypersalivation, are also often described."

Names profuse sweating as an autonomic sign of the illness.

Musculoskeletal 1

Muscle weakness FREQUENT HP:0001324

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Motor disorders, including muscle weakness and general asthenia, are common complaints"

States that motor weakness is a common complaint.

Nervous System 5

Perioral and distal paresthesia FREQUENT HP:0003401

Show evidence (3 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Neurological symptoms begin with early paresthesia on the face and especially around the mouth (lips, tongue), then rather involve the extremities."

States the perioral-then-distal distribution this phenotype records.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Among the sensory disturbances, in most cases, three particular signs are characteristic: paresthesia, cold dysesthesia and pruritus."

Supports the diagnostic-triad claim, and is the basis for the FREQUENT grading - "in most cases" is a majority statement, not the 80% the VERY_FREQUENT band requires.

PMID:29449664 SUPPORT Human Clinical

"93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."

Puts a number on it: neurological signs in 76.0% of 234 cases, with paresthesia named first.

Hyperesthesia HP:0100963

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"superficial hyperesthesia with sensations of burning and electric discharges"

Names the sign and the qualities this description records.

Headache HP:0002315

Show evidence (1 reference)

PMID:28867800 SUPPORT BACKGROUND Human Clinical

"distressing, often persistent sensory disturbances such as perioral and distal paresthesias, dysesthesias, pruritus, headache, asthenia, myalgia, arthralgia and tooth pain"

Lists headache among the reported symptoms.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."

Names impaired motor coordination and ataxia among the neurological signs.

Hyporeflexia HP:0001265

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."

Names the reflex change. `HP:0001265` Hyporeflexia covers the reduction; the abolition the same sentence reports would be areflexia (`HP:0001284`), and the source gives no basis for splitting the two, so the reduced-reflex term is bound and the fuller phrase kept in `preferred_term`.

Constitutional 5

Abdominal pain VERY_FREQUENT HP:0002027

Temporal: ACUTE

Show evidence (1 reference)

PMID:29449664 SUPPORT Human Clinical

"93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."

Quantifies the gastrointestinal syndrome this phenotype belongs to at 93.9% of 234 cases, which is the basis for the VERY_FREQUENT grading across the gastrointestinal block.

Cold allodynia VERY_FREQUENT HP:0012533

HPO has no cold-specific allodynia term - a search of HP labels returns `HP:0012533` Allodynia, `HP:0012534` Dysesthesia and `HP:0010829` Impaired temperature sensation, none of which names cold-evoked pain. Allodynia is bound because the defining feature is pain from a normally non-painful stimulus, and the cold qualifier is carried in `preferred_term` rather than manufactured as a narrower ontology match.

Show evidence (3 references)

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold."

Source of both the phenomenology and the correction to the temperature-reversal wording.

PMID:28867800 SUPPORT BACKGROUND Human Clinical

"temperature dysesthesia, or cold allodynia, a pathophysiological condition where innocuous cold is perceived as painful burning of the skin, is considered pathognomonic and occurs in up to 95% of ciguatera sufferers."

Supports both the pathognomonic status and the VERY_FREQUENT grading.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Painful sensations on contact with cold (cold dysesthesia) appear mostly within the first 2 days."

Establishes the timing stated in this description.

Myalgia FREQUENT HP:0003326

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Myalgia, especially in the muscles of the legs, is also frequently reported, as well as other sensory disorders, including a metallic taste"

States the myalgia and its leg predominance.

Arthralgia HP:0002829

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"arthralgia mainly affecting the large joints (knees, ankles, shoulders and elbows)"

States the joint distribution recorded here.

Fatigue FREQUENT HP:0012378

Show evidence (1 reference)

PMID:34564650 SUPPORT Human Clinical

"mostly under the traits of neurological and psychiatric disorders (i.e., tenacious fatigue, paraesthesia, dysesthesia, pruritus, attention deficit disorder, anxiety, depression)"

Names fatigue first among the persisting manifestations.

💊

Medical Actions

5

Supportive and symptomatic care

Action: Supportive Care NCIT:C15747

First-line and the only universally agreed management. Rehydration for gastrointestinal losses, antiemetics and antidiarrhoeals, analgesia for myalgia and arthralgia, antihistamines for pruritus, and atropine plus fluid and vasopressor support for bradycardia and hypotension. Rehydration also has to precede any mannitol infusion.

Target Phenotypes: Diarrhea HP:0002014 Hypotension HP:0002615

Show evidence (3 references)

PMID:25333356 SUPPORT Human Clinical

"Treatment of ciguatera is primarily supportive and symptomatic."

States supportive care as the mainstay.

PMID:36006197 SUPPORT Human Clinical

"Management was supportive. No patient died but symptoms persisted in 40% of the 77 patients with follow-up at day 15."

Records what was actually given across a 149-patient series, together with the outcome - no deaths, but persisting symptoms in 40% of those followed up.

PMID:19005579 SUPPORT REVIEW SYNTHESIS Human Clinical

"indicated that mannitol should not be administered until the patient is adequately rehydrated"

Supports rehydration preceding mannitol, which is the ordering claim in this description.

Intravenous mannitol

Action: Pharmacotherapy NCIT:C15986

Agent: mannitol CHEBI:16899

Platform: Small molecule

The most studied specific intervention and a genuinely contested one. Uncontrolled case series, an unblinded comparative trial and many case reports describe rapid neurological improvement when mannitol is given early; the single randomised controlled trial found no difference from normal saline. The proposed mechanism - osmotic reversal of the neuronal oedema this entry records as nodal and adaxonal swelling - is supported in isolated nerve preparations but not in intact animals. Both positions are recorded below rather than resolved.

Mechanism Target:

Nodal and Adaxonal Schwann Cell Swelling — The proposed target: hyperosmolar mannitol reverses the osmotic swelling at the node.

Show evidence (2 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS In Vitro

"nodal swelling of myelinated nerve fibers was prevented by tetrodotoxin and completely prevented and reversed by pretreatment with or the addition of hyperosmolar external solutions of D-mannitol"

Demonstrates that hyperosmolar mannitol reverses this specific lesion in nerve fibres.

PMID:28535116 REFUTE REVIEW SYNTHESIS Model Organism

"Treatment with mannitol fails to correct these effects."

The same reversal does not happen in an intact animal - in rats given intraperitoneal ciguatoxin, mannitol failed to correct the increased refractory period and slowed conduction velocity. This is why the treatment description says the mechanism is supported in isolated nerve preparations but not in intact animals.

Show evidence (4 references)

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"Evidence supporting mannitol for ciguatera fish poisoning includes four uncontrolled case series, one prospective, unblinded comparative trial and several case reports."

The body of evidence favouring mannitol, and its design limitations.

PMID:28535116 REFUTE REVIEW SYNTHESIS Human Clinical

"In 2002, a small randomized, controlled trial reported no significant difference between mannitol and normal saline."

The only randomised evidence, and it contradicts the claim that mannitol is effective. Recorded as a separate REFUTE item rather than folded into the supporting one, because the two quotes make opposite claims.

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"It is reasonable to consider using intravenous mannitol in cases of acute ciguatera fish poisoning."

The reviewers' net position after weighing both bodies of evidence.

+ 1 more reference

Atropine for symptomatic bradycardia

Action: Pharmacotherapy NCIT:C15986

Agent: atropine CHEBI:16684

Platform: Small molecule

The specific pharmacologic intervention for the one life-threatening feature of the illness, given with intravenous fluids and dopamine. Reversal can need unusually large cumulative doses over days - 45 mg and 30 mg over 48 hours in the two published cases - so a persisting bradycardia is a reason to continue rather than to abandon it.

Target Phenotypes: Bradycardia HP:0001662

Show evidence (3 references)

PMID:25333356 SUPPORT Human Clinical

"Severe bradycardia and prolonged hypotension can occur, necessitating prompt treatment with intravenous atropine, intravenous fluid replacement and dopamine infusion"

States the indication and the three-drug combination this treatment records.

PMID:22574244 SUPPORT Human Clinical

"A continuous infusion of atropine with a total dose of 45 mg over 48 hours was given."

Source of the cumulative-dose figure in this description.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"atropine effectively relieves the gastrointestinal and cardiovascular disturbances"

Independent statement that atropine works here, which is why this entry no longer describes the bradycardia as atropine-resistant.

Neuropathic-pain pharmacotherapy for persistent symptoms

Action: Pharmacotherapy NCIT:C15986

Agent: amitriptyline CHEBI:2666 gabapentin CHEBI:42797 pregabalin CHEBI:64356 duloxetine CHEBI:36796 fluoxetine CHEBI:5118 tocainide CHEBI:9611

Platform: Small molecule

Amitriptyline, gabapentin, pregabalin, fluoxetine, duloxetine and tocainide have all been reported to suppress the paresthesia, dysesthesia and pruritus of the chronic phase. The evidence is case reports and overlapping case series only, none has been shown superior to another, and a long duration of treatment appears necessary to maintain the benefit.

Mechanism Target:

Repetitive Firing of Peripheral Sensory Afferents — These are the agents used for neuropathic pain generally, and the persisting paresthesia and dysesthesia they suppress here are the clinical expression of this node. Whether they act on this mechanism in ciguatera specifically has not been shown.

Show evidence (1 reference)

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases."

States the observed effect. It supports the symptom claim; the mechanism attribution in this link's description is an inference and is flagged as such.

Target Phenotypes: Perioral and distal paresthesia HP:0003401 Pruritus HP:0000989

Show evidence (3 references)

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"Evidence regarding other treatments consists only of ten case reports and three overlapping case series that describe using amitriptyline, fluoxetine, duloxetine, gabapentin, pregabalin, or tocainide."

Names the agents and states the quality of evidence behind them.

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases."

States the effect claimed for this treatment class.

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"However, the human evidence is of low quality for all treatments."

The caveat this description carries, in the reviewers' own words.

Avoidance of relapse-triggering foods

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Patients are counselled to avoid reef fish and other marine products, alcohol, nuts and red meat after an episode, because these are reported to reactivate neurological symptoms months after the index poisoning. The trigger list is observational and the mechanism is unknown.

Show evidence (1 reference)

PMID:34564650 SUPPORT Human Clinical

"These manifestations can be expressed continuously or through transient reactivation peaks, triggered by multiple factors (e.g., consumption of marine/fresh water-related products, even from non-endemic region, alcohol, nuts, and red meat."

Names the triggers this avoidance advice is built on.

🌍

Environmental Factors

2

Consumption of ciguatoxin-contaminated carnivorous reef fish

Hazard type: CHEMICAL

Route: ORAL

Duration: ACUTE

Bound to `ECTO:0000537` exposure to toxin. ECTO was searched through this repository's adapter (`sqlite:obo:ecto`) for a ciguatoxin or ciguatera exposure class and none exists. The nearest classes under `ECTO:0000537` are mycotoxin, phytoalexin, phytotoxin, nephrotoxin, uremic toxin and virulence factor, and the fish-ingestion classes that do exist (`ECTO:0070099` bluefish, `ECTO:0070100` swordfish, `ECTO:0070189` whitefish, `ECTO:0070209` dark fish flesh) name unrelated species. One algal-toxin class does exist outside that subtree - `ECTO:8000033` exposure to accumulation of toxins from algal bloom process, whose parent is `ECTO:8000000` exposure to environmental process, so a descendant walk from `ECTO:0000537` misses it. It was considered and not used: ciguatoxin reaches people through years of food-chain accumulation in fish, not through a bloom event, and this entry's exposure is a meal rather than an environmental process. The specific agent is carried in `preferred_term`, and the toxin itself is bound to `CHEBI:61275` on the pathophysiology nodes where it acts. `food_source` names the marine fish product class rather than a species, because the implicated species differ by ocean basin and the slot takes a single term.

The sole route of exposure. Carnivorous reef predators - jacks and trevallies, snappers, groupers, barracuda, moray eels, amberjack and king mackerel - carry the highest toxin burden because the toxin biomagnifies up the reef food chain, and liver, roe and viscera concentrate it further. Contaminated fish are indistinguishable from safe ones by taste, smell or appearance, and the toxins survive cooking, salting and freezing, so no consumer-level precaution short of avoiding the species removes the risk.

Show evidence (3 references)

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels."

Names the implicated species and the undetectability that this description rests on.

PMID:36006197 SUPPORT Human Clinical

"CP was mainly attributed to the ingestion of trevallies (59%), snappers (13%), and king mackerels (8%)"

Quantifies which species actually caused disease in one Caribbean series, which is a stronger claim than a list of high-risk species.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"Ciguateric fish are indistinguishable from uncontaminated ones with regard to taste, smell, and appearance."

Supports the claim that no consumer-level inspection detects the exposure.

Mechanism Target:

TRIGGERS Ingestion and Systemic Distribution of Ciguatoxin — The meal is what delivers the toxin the whole entry follows from.

Show evidence (1 reference)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs)."

States consumption of contaminated fish as the cause of the disease.

Sea surface warming and coral reef disturbance

`exposure_term` deliberately carries a free-text `preferred_term` with no `term:`. ECTO was searched for a sea-surface-temperature, ocean-warming or reef-degradation exposure class and none exists; the temperature classes available describe exposure of an organism to ambient heat, which is not the claim here - the warming acts on the dinoflagellate habitat, not on the patient. `ECTO:0000537` would be wrong for the same reason, since no toxin is being described at this step.

Reef degradation and rising sea surface temperatures expand the algal substrate that Gambierdiscus and Fukuyoa colonise and extend the geographic range in which ciguatera occurs, including into previously unaffected temperate-adjacent waters. This acts on the upstream production step rather than on the human host.

Show evidence (3 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"global warming has tended to extend the areas concerned"

States the range-expansion claim in this description.

PMID:28225079 SUPPORT BACKGROUND Other

"oceans warm and algal blooms become more frequent, ciguatera is now emerging as a significant issue in Asia, America and parts of Europe"

Ties ocean warming and bloom frequency directly to the geographic expansion this exposure describes, rather than the expansion alone.

PMID:29449664 SUPPORT Human Clinical

"The monitoring of ciguatera poisoning throughout the Caribbean region must be improved, notably after reef disturbance due to Irma and Maria major cyclones."

A surveillance recommendation, not a measurement. It is included because it shows investigators treating named cyclone reef disturbance as a reason to expect changed ciguatera risk, which is weaker than demonstrating it.

Mechanism Target:

PREDISPOSES Gambierdiscus Ciguatoxin Production on Reef Substrate — Warming and reef disturbance change where and how much toxin-producing dinoflagellate is present, which sets regional risk rather than causing an individual poisoning.

Show evidence (2 references)

PMID:41610130 SUPPORT Other

"When CTXs accumulate in seafood they cause Ciguatera Poisoning (CP), which affects ca. 20-50,000 people p.a. and is likely worsened by climate change."

States climate change as a worsening factor for the disease, which is this link.

PMID:33066435 SUPPORT REVIEW SYNTHESIS Other

"global warming has tended to extend the areas concerned"

States the geographic consequence directly - warming extends where the disease occurs, which is what this PREDISPOSES link asserts.

🔬

Diagnosis

3

Clinical diagnosis from exposure history and syndrome

There is no confirmatory bedside test. The diagnosis rests on a recent reef-fish meal plus the characteristic sequence - gastrointestinal upset followed by paresthesia, cold allodynia and pruritus - in a non-febrile patient, supported where possible by analytical testing of a remnant of the fish that was eaten.

Show evidence (2 references)

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of CFP is based on the recent fish-eating history of the patient(s), clinical presentation, and whenever possible, results from analytical testing of a remnant of the fish consumed by the person(s) suffering from CFP."

States all three legs of the diagnosis this entry records.

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients diagnosed with CFP without fish testing confirmation should be warned about the uncertainty of a purely clinical diagnosis and recommended for additional medical evaluation if symptoms recur or do not resolve."

Records how uncertain a clinical-only diagnosis is held to be, which is why fish testing matters.

Absence of a human biomarker of ciguatoxin exposure (absent)

The gap that shapes everything else about diagnosing this disease. Nothing measurable in the patient confirms exposure, so every assay below is applied to the fish rather than to the person, and the clinical diagnosis cannot be laboratory-confirmed in the patient at all.

Show evidence (2 references)

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"There are currently no identified biomarkers that can be used to confirm exposure to CTX in humans"

States the absence directly.

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"The development of methods to confirm exposure to CTX in affected humans will assist not only in the diagnostic process, but also in the validity of clinical trials investigating treatments for individuals with a presumed CFP diagnosis."

Names the downstream consequence that matters for this entry - it is also why the treatment evidence recorded here is as weak as it is.

Ciguatoxin detection in the implicated fish

The analytical work is done on fish tissue. The FDA protocol is a two-tier screen-then-confirm design: an N2a mouse neuroblastoma cell assay for activity consistent with the ciguatoxin mode of action, then LC-MS/MS for molecular confirmation. Receptor-binding assays and ELISA are the main alternatives, and the historical mouse bioassay is being displaced on welfare and specificity grounds.

Show evidence (3 references)

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"in vitro mouse neuroblastoma (N2a) cell assay as a semi-quantitative screen for toxicity consistent with CTX mode of action; and (2) liquid chromatography tandem-mass spectrometry (LC-MS/MS) for molecular confirmation of CTX."

The two tiers of the regulatory protocol this diagnosis entry describes.

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"Alternative methods for CTX detection in fish include receptor binding assays"

Names the alternative assay class recorded here.

PMID:18623118 SUPPORT In Vitro

"The applicability of a new enzyme-linked immunoassay (ELISA) for detecting ciguatoxin (CTX) in fish tissue was evaluated by testing three fish species commonly implicated in ciguatera fish poisoning in Hawaii."

A worked example of the ELISA route, applied to fish tissue rather than to a patient.

📈

Progression

3

Acute gastrointestinal phase

Duration: 1-2 days Incubation: 1 days

Onset is a few minutes to 24 hours after the meal, and falls between one and six hours in 90% of cases. `incubation_days: 1` is the coarse day-granularity encoding of that sub-day latency; the verbatim range is in the evidence below.

Show evidence (2 references)

PMID:33066435 SUPPORT REVIEW SYNTHESIS Human Clinical

"The first symptoms appear a few minutes to 24 h after the toxic fish meal, but occur between 1 and 6 h in 90% of cases"

Establishes the latency of this phase.

PMID:26454262 SUPPORT BACKGROUND Human Clinical

"The gastrointestinal effects are typically transient (1–5 days), whereas neurological symptoms can persist for weeks to many months"

Establishes that this phase is transient and separates it from the neurological one.

Acute neurological and cardiovascular phase

Duration: days to weeks

Overlaps with or shortly follows the gastrointestinal phase. Sensory disturbance dominates; cardiovascular signs when present appear in the first day.

Show evidence (1 reference)

PMID:25333356 SUPPORT Human Clinical

"In affected subjects, the gastrointestinal symptoms often subside within days, whereas the neurological symptoms can persist for weeks or even months."

Contrasts the duration of this phase with the preceding one.

Chronic ciguatera

Duration: 3 months or longer

Defined in the literature as symptoms lasting three months or more, affecting at least a fifth of patients. Manifestations are mainly neurological and psychiatric - tenacious fatigue, paresthesia, dysesthesia, pruritus, anxiety and depression - and may be continuous or appear as reactivation peaks triggered by marine or fresh-water foods, alcohol, nuts or red meat.

Show evidence (3 references)

PMID:34564650 SUPPORT Human Clinical

"Chronic forms of CP with symptoms lasting ≥3 months are a real clinical challenge."

Establishes the three-month definition this phase uses.

PMID:34564650 SUPPORT Human Clinical

"Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"

Quantifies how many patients reach this phase.

PMID:34564650 SUPPORT Human Clinical

"Ciguatera poisoning is a globally occurring seafood disease caused by the ingestion of marine products contaminated with dinoflagellate produced neurotoxins. ... Among all studied variables, five significant predictors of having symptoms lasting ≥3 months were identified: age, tobacco..."

Connects the chronic ciguatera duration studied in the hospitalized cohort to the paper’s reviewed background on persistent manifestations, reactivation triggers and frequency. The background estimate is not a new prevalence measurement from the 49-patient cohort.

📊

Prevalence

4

Hong Kong, 1989-2008

Annual Incidence 1.02 per 100,000 (0.33–6.49) per year 1–9 per 100,000 per year

Reported as 3.3-64.9 per million per year, median 10.2 per million; normalised here by dividing by ten. The band reflects the median, 1.02 per 100,000 per year.

Show evidence (1 reference)

PMID:25333356 SUPPORT Human Clinical

"From 1989 to 2008, the annual incidence of ciguatera varied between 3.3 and 64.9 (median 10.2) per million people."

Source of the rate and its range.

Guadeloupe, French West Indies, 2013-2016

Annual Incidence 14.7 per 100,000 (12.9–16.6) per year 1–9 per 10,000 per year

Reported as a mean annual incidence of 1.47 per 10,000 with a 95% confidence interval of 1.29-1.66, about five times the incidence reported for the same territory in 1996-2006.

Show evidence (1 reference)

PMID:29449664 SUPPORT Human Clinical

"Two hundred and thirty-four cases of poisoning were observed, with a mean annual incidence of 1.47/10,000"

Source of the rate and the case count behind it.

Martinique, French West Indies, 2012-2018

Annual Incidence 6.7 per 100,000 person-years 1–9 per 100,000 per year

Reported as 0.67 cases per 10,000 patient-years. The denominator is person-time as published, not population-per-year, so it is not directly comparable with the Guadeloupe figure above despite the neighbouring geography.

Show evidence (1 reference)

PMID:36006197 SUPPORT Human Clinical

"CP incidence was 0.67 cases per 10,000 patient-years in Martinique over the study period."

Source of the rate and its stated denominator.

Worldwide

Cases In Literature Unknown

Global burden is quoted as tens of thousands of cases per year, but as an absolute count with no denominator, so it is recorded here as a literature case count rather than as a rate. Every source that gives a figure also says it is a substantial underestimate.

Show evidence (2 references)

PMID:34564650 SUPPORT Human Clinical

"this would affect 10,000 to 50,000 persons every year"

One of the commonly quoted global burden figures.

PMID:41610130 SUPPORT Other

"When CTXs accumulate in seafood they cause Ciguatera Poisoning (CP), which affects ca. 20-50,000 people p.a. and is likely worsened by climate change."

An independent estimate in the same order of magnitude. Graded OTHER, as the same sentence is graded on the climate link it also carries; the quoted sentence is a marine-science paper's framing rather than a clinical series.

⚖️

Clinical Burden

Moderate

Case fatality is very low and most acute illness resolves within days to weeks, but the neurological phase routinely outlasts the gastrointestinal one by months, a substantial minority develop a chronic relapsing syndrome, and the burden falls on reef-dependent island communities with limited diagnostic and therapeutic options.

Show evidence (2 references)

PMID:19005579 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world, and it causes substantial physical and functional impact."

States both the global frequency and the functional impact behind this burden level.

PMID:34564650 SUPPORT Human Clinical

"Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"

Quantifies the chronic tail that keeps this above a purely self-limited illness.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Ciguatera Fish Poisoning:

Other marine and fish-borne toxin syndromes

Overlapping Features Ciguatera shares symptoms with paralytic, neurotoxic and diarrhetic shellfish poisoning, scombrotoxin (histamine) fish poisoning, pufferfish tetrodotoxin poisoning and hallucinatory fish poisoning. All arrive through the same "I ate seafood and got sick" history, so the exposure story does not discriminate between them.

Distinguishing Features

Cold allodynia - burning pain on innocuous cold contact - is the discriminating feature, and is described as pathognomonic for ciguatera.
The implicated species differs: ciguatera follows carnivorous reef fish (jacks, groupers, snappers, barracuda, moray eels, amberjack).

Show evidence (2 references)

PMID:28335428 SUPPORT REVIEW SYNTHESIS Human Clinical

"CFP induces some symptoms in common with paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), scombrotoxin fish poisoning, pufferfish poisoning (also referred to as Fugu poisoning), and hallucinatory fish poisoning"

Names the differential this entry records.

PMID:28535116 SUPPORT REVIEW SYNTHESIS Human Clinical

"The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold."

Supports cold allodynia as the discriminating feature. Its specificity against the other syndromes named here is not quantified in any source cited by this entry, so "near-pathognomonic" is the clinical consensus rather than a measured test characteristic.

🐁

Animal Models

2

Cook Islands naturally occurring canine and feline ciguatera Natural disease

Not an engineered model. Dogs and cats in Rarotonga eat reef fish and fish scraps and develop ciguatera in numbers large enough to study: 246 cases in six years of records from the only veterinary clinic in the territory, 165 dogs and 81 cats. The presentation is motor-dominant - ataxia, paresis and recumbency - rather than the sensory-dominant syndrome seen in people, which is the main reason this is recorded as partially recapitulating rather than recapitulating.

Species

Dog

Publication

PMID:32158145

Pathograph links

Ingestion and Systemic Distribution of Ciguatoxin partially recapitulates fidelity: moderate observes: organism The same exposure route and the same toxin, in a naturally exposed non-human population with veterinary follow-up that human series rarely match.

Limitations: The clinical picture diverges from the human one: motor signs dominate and the sensory disturbances that define human ciguatera cannot be elicited from an animal at all, so the syndrome is not comparable symptom by symptom. Dose is unmeasured and probably higher than a human meal, because these animals scavenge viscera and whole carcasses where the toxin concentrates. No toxin assay confirmed exposure in individual cases; the case definition is clinical.

Show evidence (3 references)

PMID:32158145 SUPPORT Model Organism

"A total of 246 cases of CFP were identified, comprising 165 dogs and 81 cats."

Establishes the scale of the naturally exposed population this model rests on.

+ 2 more references

Recorded under a single `species: Dog` entry although the source series covers dogs and cats together; the slot takes one value and dogs are the larger group. The feline cases are described in the same papers and the quoted findings are reported for both species.

Show evidence (2 references)

PMID:32848300 SUPPORT Model Organism

"The survival rate was >90% and almost all mortalities occurred in the first week of hospitalization."

Outcome data from the same population, which parallels the low human case fatality and supports treating the animal disease as informative.

PMID:32848300 SUPPORT Model Organism

"The treatments most commonly administered to cases were fluid therapy and muscle relaxants."

Records that management was supportive here too, as in humans.

Rat spinal dorsal horn ciguatoxin cold hypersensitivity model Induced

Subcutaneous Pacific ciguatoxin-2 into the receptive field of a dorsal horn wide-dynamic-range neuron, with in vivo electrophysiological recording of responses to cooling. This is the model that assigned ciguatera cold allodynia to Nav1.8 and TRPA1 rather than to the canonical cold receptor TRPM8.

Species

Rat

Publication

PMID:26454262

Pathograph links

Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents recapitulates fidelity: moderate observes: cellular Local ciguatoxin reproduces the cold hypersensitivity, and the channel dependence is established by selective antagonists.

Limitations: The readout is a spinal neuronal firing rate in a non-sentient preparation, not a reported sensation, so the mapping onto human cold allodynia is an inference the authors make explicitly rather than a measurement. The toxin is injected locally at a known concentration rather than ingested and distributed, so absorption, congener mixture and dose are all bypassed.

Readouts

Dorsal horn neuronal response to innocuous and noxious cooling

Direction: INCREASED

Interpretation: Increased firing to cooling after local ciguatoxin is the electrophysiological correlate of cold allodynia.

Show evidence (1 reference)

PMID:26454262 SUPPORT Model Organism

"Subcutaneous injection of 10 nm ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling."

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:26454262 SUPPORT Model Organism

"Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav 1.8/TRPA1-positive primary afferents, which could underlie the cold allodynia reported in ciguatera."

The authors' own statement that this model informs the human sign.

Show evidence (2 references)

PMID:26454262 SUPPORT Model Organism

"This study examined, for the first time, the neural substrates and molecular components of Pacific ciguatoxin-2-induced cold hypersensitivity."

States what the preparation was built to measure, which is what makes it a model of this entry's cold-sensitisation node.

PMID:26454262 SUPPORT Model Organism

"Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non-sentient rats."

Records the preparation and readout this model entry describes.

{ }

Source YAML

click to show

name: Ciguatera Fish Poisoning
creation_date: "2026-09-15T02:30:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Marine Biotoxin Illness
- Foodborne Intoxication
parents:
- Foodborne Intoxication
- Marine Biotoxin Poisoning
synonyms:
- ciguatera
- ciguatera poisoning
- CFP
- ciguatoxin poisoning
- ciguatera toxicosis
description: >-
  Ciguatera fish poisoning is an acquired foodborne intoxication caused by eating
  reef fish whose flesh carries ciguatoxins - lipophilic, heat-stable cyclic
  polyether toxins originating in the benthic dinoflagellates Gambierdiscus and
  Fukuyoa. The algal precursors, gambiertoxins, enter the reef food web when
  herbivorous fish graze toxin-bearing macroalgae, are oxidised in fish liver to
  more polar and more potent congeners, and biomagnify into carnivorous
  predators such as jacks, groupers, snappers, barracuda and moray eels. Because
  the toxins are tasteless, odourless and unaffected by cooking or freezing, no
  consumer-level inspection prevents exposure. The unifying molecular mechanism
  is binding at neurotoxin receptor site 5 on the alpha subunit of voltage-gated
  sodium channels, which shifts the voltage dependence of activation to more
  hyperpolarised potentials and impairs inactivation, so channels open near the
  resting membrane potential. The resulting sodium influx, amplified by
  concurrent block of delayed-rectifier and A-type potassium currents, drives
  repetitive firing in peripheral sensory afferents, enteric and autonomic
  neurons, and cardiac conduction tissue, and produces osmotically driven
  swelling at the nodes of Ranvier and in adaxonal Schwann cell cytoplasm.
  Patients present within hours of the meal with nausea, vomiting, diarrhoea and
  abdominal pain, followed by perioral and distal paresthesia, pruritus and the
  near-pathognomonic cold allodynia in which innocuous cool contact is felt as
  burning pain; bradycardia and hypotension occur in a minority and can be
  life-threatening. Gastrointestinal features settle within days while
  neurological features persist for weeks to months, and roughly a fifth of
  patients develop a chronic relapsing syndrome of fatigue, dysesthesia and
  pruritus that can be reactivated by alcohol, nuts or a further fish meal. No
  antidote exists; management is supportive, with intravenous mannitol and
  neuropathic-pain agents both supported only by low-quality evidence.
notes: >-
  Curated from a `claude_code` deep-research report
  (`research/Ciguatera_Fish_Poisoning-deep-research-claude_code.md`), whose
  reference validation resolved 38/38 identifiers and whose term validation
  resolved 41/41 CURIEs. Every ontology binding written here was nevertheless
  re-derived by a fresh lookup rather than copied from that report, per the
  repository's term contract; the report itself flags its suggested CURIEs as
  unverified. There is no GeneReviews chapter, and no OMIM entry, because this
  is an acquired toxicosis with no Mendelian basis - the `genetic:` section is
  deliberately absent rather than empty, and the open question of host
  voltage-gated sodium channel variation is recorded in `discussions` instead of
  being inferred from channel pharmacology. `clinical_trials:` is likewise empty
  because no NCT-registered ciguatera trial was found; the one randomised trial
  in the literature predates registration and is cited through the review that
  appraises it.

  Two mechanisms here are genuinely disputed and are curated as disputes rather
  than resolved. Where ciguatoxin acts on the heart is one: the clinical
  literature argues an indirect vagal-afferent and central-vasomotor route while
  mouse histology argues direct myocardial sodium channel activation, and the
  `Cardiac Conduction and Vasomotor Disturbance` node carries both with a
  `REFUTE` item against the indirect account. Whether intravenous mannitol works
  is the other, carried as a `SUPPORT`/`REFUTE` pair on the treatment and a
  second `REFUTE` on its mechanism link, where the nerve-preparation result and
  the intact-rat result disagree.

  Two causal edges are deliberately *not* drawn. Sodium channel activation does
  not cause the potassium current inhibition, so that node hangs off the
  ingestion node as a parallel branch of the same exposure; and repetitive
  firing does not cause the cold sensitisation, which is a sibling consequence
  of the same depolarisation. Both were initially drawn the wrong way round and
  corrected.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0043230
      label: ciguatera fish poisoning
    mapping_predicate: skos:exactMatch
    mapping_justification: semapv:ManualMappingCuration
  icd10cm_mappings:
  - term:
      id: ICD10CM:T61.0
      label: Ciguatera fish poisoning
    mapping_predicate: skos:exactMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      ICD-10-CM codes this disease by name at T61.0, subdivided by intent and
      encounter (T61.01XA accidental/initial, T61.01XD subsequent, T61.01XS
      sequela, plus intentional, assault and undetermined branches). The
      undivided parent is bound here because the intent and encounter axes are
      administrative rather than nosological.
disease_term:
  preferred_term: ciguatera fish poisoning
  term:
    id: MONDO:0043230
    label: ciguatera fish poisoning
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    Case fatality is very low and most acute illness resolves within days to
    weeks, but the neurological phase routinely outlasts the gastrointestinal
    one by months, a substantial minority develop a chronic relapsing syndrome,
    and the burden falls on reef-dependent island communities with limited
    diagnostic and therapeutic options.
  evidence:
  - reference: PMID:19005579
    reference_title: "Ciguatera fish poisoning: treatment, prevention and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world, and it causes substantial physical and functional impact."
    explanation: States both the global frequency and the functional impact behind this burden level.
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"
    explanation: Quantifies the chronic tail that keeps this above a purely self-limited illness.
pathophysiology:
- name: Gambierdiscus Ciguatoxin Production on Reef Substrate
  biological_scale: ORGANISM
  description: >-
    The environmental origin of the toxin. Benthic dinoflagellates of the genera
    Gambierdiscus and Fukuyoa live epiphytically on macroalgae, dead coral and
    reef detritus in tropical and subtropical waters, where they synthesise the
    ciguatoxin precursors known as gambiertoxins. Toxin production is
    species-specific rather than a property of the genus as a whole, which is
    why Gambierdiscus abundance alone is a poor predictor of local risk.
  notes: >-
    Deliberately carries no ontology-bound process descriptor. The node denotes
    a process occurring in a free-living marine microalga, not in the human
    host, and the GO terms available describe host-side biology.
  downstream:
  - target: Trophic Biotransformation and Biomagnification in Reef Fish
    causal_link_type: DIRECT
    description: >-
      Algal gambiertoxins enter the reef food web when herbivorous fish graze
      the substrate the dinoflagellates colonise.
    evidence:
    - reference: PMID:28225079
      reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "Consumption of coral and seaweed contaminated with Gambierdiscus by herbivorous fish leads to bioaccumulation of the ciguatoxins through the food chain via larger carnivorous fish that in turn are consumed by humans and cause ciguatera."
      explanation: States the grazing step that carries algal toxin into the food chain, which is this edge.
  evidence:
  - reference: PMID:41610130
    reference_title: "Risk of ciguatoxins is shaped by Gambierdiscus community structure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ciguatoxins (CTXs) are produced by marine microbial eukaryotes (Gambierdiscus/Fukuyoa, Dinophyta: Alveolata) that live epiphytically on macroalgae and other substrates."
    explanation: Establishes the producing organisms and the substrate they occupy.
  - reference: PMID:41610130
    reference_title: "Risk of ciguatoxins is shaped by Gambierdiscus community structure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Of newly isolated Gambierdiscus strains, only the three G. polynesiensis produced P-CTXs."
    explanation: >-
      Supports the species-specificity point in this description - most isolates
      from an endemic site made no Pacific ciguatoxin at all.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "These toxins originate from benthic microalgae of the genus Gambierdiscus and Fukuyoa"
    explanation: Independent statement of the algal origin of the toxins.
- name: Trophic Biotransformation and Biomagnification in Reef Fish
  biological_scale: ORGANISM
  description: >-
    Gambiertoxins taken up by herbivorous fish are oxidised by fish hepatic
    cytochrome P450 enzymes into more polar and substantially more potent
    ciguatoxin congeners, and accumulate as those fish are eaten by carnivorous
    predators. The end products differ by ocean basin - P-CTX-1 in the Pacific,
    C-CTX-1/2 in the Caribbean, I-CTX in the Indian Ocean - and the Pacific end
    product is the most toxic congener known for mammals.
  chemical_entities:
  - preferred_term: ciguatoxin
    term:
      id: CHEBI:61275
      label: ciguatoxin
  downstream:
  - target: Ingestion and Systemic Distribution of Ciguatoxin
    causal_link_type: DIRECT
    description: >-
      The concentrated toxin burden in predatory reef fish flesh is what a human
      meal delivers.
    evidence:
    - reference: PMID:28535116
      reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels."
      explanation: >-
        Connects food-chain accumulation to the carnivorous fish that people
        actually eat, which is the step this edge asserts.
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "During this transfer, GTXs are not only accumulated within the marine food chain but also biotransformed to become more polar and more toxic CTXs"
    explanation: States both halves of this node - accumulation and toxifying biotransformation.
  - reference: PMID:37044143
    reference_title: "Algal ciguatoxin identified as source of ciguatera poisoning in the Caribbean."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Metabolism in vitro by fish liver microsomes converted algal C-CTX5 into C-CTX1/2, the dominant CTX in ciguatoxic fish from the Caribbean."
    explanation: >-
      Direct demonstration that fish hepatic metabolism performs the
      algal-precursor to fish-congener conversion this node asserts.
  - reference: PMID:28867800
    reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The precursors are oxidized to CTXs in the fish liver by cytochrome enzymes to become the most potent mammalian voltage-gated sodium channel (VGSC) toxins known."
    explanation: Names the enzymatic route and the resulting increase in mammalian potency.
- name: Ingestion and Systemic Distribution of Ciguatoxin
  biological_scale: ORGANISM
  description: >-
    The exposure event. A human meal of contaminated reef fish delivers
    ciguatoxin that cannot be detected by taste, smell or appearance and is not
    destroyed by cooking, salting or freezing. Because the toxins are lipophilic
    they are readily absorbed and slowly eliminated, and distribute to excitable
    tissue throughout the body.
  notes: >-
    Carries no ontology-bound process descriptor: the node denotes an exposure
    event rather than a host biological process. The exposure itself is grounded
    in the `environmental:` block.
  downstream:
  - target: Voltage-Gated Sodium Channel Site 5 Activation
    causal_link_type: DIRECT
    description: >-
      Absorbed ciguatoxin reaches voltage-gated sodium channels in peripheral
      nerve, enteric and autonomic neurons, and cardiac tissue.
  - target: Potassium Current Inhibition in Sensory Neurons
    causal_link_type: DIRECT
    description: >-
      The same absorbed toxin independently reaches potassium conductances in
      dorsal root ganglion neurons. This is a parallel branch of the exposure,
      not a consequence of the sodium lesion: ciguatoxin acting on one channel
      class does not cause its action on the other, and the two converge
      downstream at afferent firing rather than one feeding the other.
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs)."
    explanation: Establishes fish consumption as the causal exposure for the disease.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CTXs are thermo- and relatively acid- and basic-stable toxins that are unaffected by cooking, salting or congealing"
    explanation: Supports the claim that ordinary preparation does not remove the exposure.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "lipid-soluble and therefore readily absorbed and slowly eliminated in fish and humans"
    explanation: Source of the absorption and elimination claim in this description.
- name: Voltage-Gated Sodium Channel Site 5 Activation
  biological_scale: MOLECULAR
  description: >-
    Ciguatoxins bind neurotoxin receptor site 5 on the alpha subunit of
    voltage-gated sodium channels - the same site targeted by the structurally
    related brevetoxins - and act as allosteric activators rather than blockers.
    Binding shifts the voltage dependence of activation to more hyperpolarised
    potentials and impairs inactivation, so a fraction of channels is open at or
    near the resting membrane potential. The effect is close to non-selective
    across Nav1.1 to Nav1.9, with the largest activation shifts at the
    tetrodotoxin-resistant isoforms Nav1.8 and Nav1.9.
  molecular_functions:
  - preferred_term: ciguatoxin-activated voltage-gated sodium channel activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
  chemical_entities:
  - preferred_term: ciguatoxin
    term:
      id: CHEBI:61275
      label: ciguatoxin
  notes: >-
    `modifier: GAIN_OF_FUNCTION` rather than `INCREASED` is deliberate, and
    follows the CLAUDE.md rule for a qualitative rather than quantitative claim:
    the channel is not simply more active, it is opening outside its normal
    voltage-dependent constraint. There is no host variant anywhere in this
    entry, so `functional_impact_category` has nothing to describe - the same
    situation the knowledge base records for virally driven pathway activation.
  downstream:
  - target: Sustained Sodium Influx and Membrane Depolarization
    causal_link_type: DIRECT
    description: >-
      Channels opening at resting potential admit sodium continuously rather
      than only during an action potential.
    evidence:
    - reference: PMID:26454262
      reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "likely leading to channel activation at resting membrane potentials, ongoing activity in primary sensory afferent fibres, axonal swelling and elevation of intracellular calcium"
      explanation: >-
        States the inference from the biophysical shift to resting-potential
        activation and ongoing afferent activity, which is this edge.
  evidence:
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "This diverse symptomatology is believed to be caused by the interaction of the ciguatoxins with site 5 of the voltage-gated sodium channels (NaV)"
    explanation: >-
      Names site 5 as the molecular target. Graded OTHER because the quoted
      sentence reports a mechanistic belief about a binding site and describes no
      study of its own; the direct patch-clamp measurement below is the real
      support for this node.
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "P-CTX-1 significantly shifted the V1/2 for the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes"
    explanation: >-
      Direct patch-clamp measurement of the activation shift, across every human
      Nav isoform tested.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Alterations of TTX-s Nav properties comprise a shift of the activation threshold voltage to more negative values associated with an impairment of their inactivation process"
    explanation: States the second half of the biophysical claim, impaired inactivation.
  - reference: PMID:37044143
    reference_title: "Algal ciguatoxin identified as source of ciguatera poisoning in the Caribbean."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, C-CTX5 from G. silvae was confirmed to have voltage-gated sodium-channel-specific activity."
    explanation: >-
      Confirms the same molecular target for the Caribbean congener lineage, not
      only the Pacific one.
- name: Potassium Current Inhibition in Sensory Neurons
  biological_scale: MOLECULAR
  description: >-
    Ciguatoxins also inhibit delayed-rectifier and A-type potassium currents in
    dorsal root ganglion neurons. Because these currents normally repolarise the
    membrane and damp repetitive discharge, their loss amplifies the
    excitability produced by the sodium-channel effect rather than acting
    independently of it.
  molecular_functions:
  - preferred_term: delayed rectifier potassium channel activity
    modifier: DECREASED
    term:
      id: GO:0005251
      label: delayed rectifier potassium channel activity
  - preferred_term: A-type potassium channel activity
    modifier: DECREASED
    term:
      id: GO:0005250
      label: A-type (transient outward) potassium channel activity
  cell_types:
  - preferred_term: dorsal root ganglion sensory neuron
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  downstream:
  - target: Repetitive Firing of Peripheral Sensory Afferents
    causal_link_type: DIRECT
    description: >-
      Loss of the repolarising currents that would otherwise terminate a burst.
  evidence:
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Ciguatoxins also inhibit delayed rectifier and A-type potassium currents in dorsal root ganglia neurones, resulting in further increases in neuronal excitability"
    explanation: States both the potassium-current effect and its amplifying role.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In vitro experiments of isolated neurons demonstrate that ciguatoxins produce neuronal edema, open certain sodium channels, block potassium channels, cause uncontrolled and repetitive action potentials after a stimulus."
    explanation: >-
      Independent synthesis naming potassium-channel block alongside the sodium
      effect and the repetitive firing it produces.
- name: Sustained Sodium Influx and Membrane Depolarization
  biological_scale: CELLULAR
  description: >-
    Continuous sodium entry through toxin-modified channels depolarises
    excitable cells, raises intracellular calcium, and imposes an osmotic load
    that water follows. This is the single cellular lesion from which the
    neurological, gastrointestinal and cardiovascular branches of the syndrome
    all descend.
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: INCREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  - preferred_term: membrane depolarization
    modifier: INCREASED
    term:
      id: GO:0051899
      label: membrane depolarization
  downstream:
  - target: Repetitive Firing of Peripheral Sensory Afferents
    causal_link_type: DIRECT
    description: >-
      A depolarised afferent fires without a stimulus and keeps firing after one.
    evidence:
    - reference: PMID:28535116
      reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "In vitro experiments of isolated neurons demonstrate that ciguatoxins produce neuronal edema, open certain sodium channels, block potassium channels, cause uncontrolled and repetitive action potentials after a stimulus."
      explanation: >-
        States the progression from channel opening to uncontrolled repetitive
        firing in isolated neurons, which is this edge.
  - target: Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents
    causal_link_type: DIRECT
    description: >-
      Depolarisation, not firing, is what shifts the voltage dependence of TRPA1
      activation so that cooling opens it. Cold sensitisation is therefore a
      sibling consequence of the same depolarisation as the repetitive firing,
      not a consequence of the firing itself.
    evidence:
    - reference: PMID:26454262
      reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "Thus, a cumulative effect on sodium and potassium currents would result in activation of TRPA1 upon cooling but not TRPM8."
      explanation: >-
        Derives TRPA1 cold activation from the combined ionic-conductance change,
        which is the depolarisation this node represents, and explains why TRPM8
        is spared.
  - target: Nodal and Adaxonal Schwann Cell Swelling
    causal_link_type: DIRECT
    description: >-
      Sodium entry with obligate water movement is the osmotic driver of the
      swelling.
    evidence:
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "nodal swelling of myelinated nerve fibers was prevented by tetrodotoxin and completely prevented and reversed by pretreatment with or the addition of hyperosmolar external solutions of D-mannitol"
      explanation: >-
        Tetrodotoxin prevention shows the swelling requires sodium entry, and
        reversal by a hyperosmolar solution shows it is osmotic - together the
        two halves of this edge.
  - target: Enteric and Autonomic Neuron Hyperexcitability
    causal_link_type: DIRECT
  - target: Cardiac Conduction and Vasomotor Disturbance
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "likely leading to channel activation at resting membrane potentials, ongoing activity in primary sensory afferent fibres, axonal swelling and elevation of intracellular calcium"
    explanation: Names the depolarisation, the calcium rise and the swelling that define this node.
- name: Repetitive Firing of Peripheral Sensory Afferents
  biological_scale: CELLULAR
  description: >-
    Depolarised primary afferents discharge spontaneously and repetitively, and
    respond excessively to stimuli that would normally be innocuous. Which
    isoform carries which symptom has been separated pharmacologically: Nav1.8
    block significantly decreases visceral pain behaviour while block of the
    tetrodotoxin-sensitive Nav1.7 and Nav1.6 significantly decreases cutaneous
    pain behaviour. Neither block abolishes it.
  biological_processes:
  - preferred_term: action potential
    modifier: INCREASED
    term:
      id: GO:0001508
      label: action potential
  cell_types:
  - preferred_term: peripheral sensory afferent neuron
    term:
      id: CL:3000004
      label: peripheral sensory neuron
  downstream:
  - target: Calcium-Dependent CGRP Release and Neurogenic Inflammation
    causal_link_type: DIRECT
  - target: Perioral and distal paresthesia
    causal_link_type: DIRECT
  - target: Hyperesthesia
    causal_link_type: DIRECT
  - target: Myalgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Arthralgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Joint pain travels with the myalgia in every series, but no source traces
      it to afferent hyperexcitability specifically, so the intermediates are
      recorded as unknown rather than guessed.
  - target: Muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Motor complaints are common, and depolarisation to the point of
      inexcitability is the obvious candidate route, but no cited source
      demonstrates it in ciguatera.
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Asthenia acutely and tenacious fatigue chronically. The route from
      peripheral afferent hyperexcitability to fatigue is not established; the
      edge records that the phenotype belongs to this branch of the syndrome,
      not that the mechanism is known.
  - target: Headache
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sensory ataxia from disturbed afferent input is the plausible route, but
      no source cited here distinguishes it from a cerebellar or vestibular one.
  - target: Hyporeflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Parageusia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation."
    explanation: Single-fibre recordings establishing afferent hyperexcitability as the cellular lesion.
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."
    explanation: Supports the isoform-to-symptom mapping this description states.
- name: Nodal and Adaxonal Schwann Cell Swelling
  biological_scale: CELLULAR
  description: >-
    Sodium entry with obligate water movement swells the nodes of Ranvier of
    myelinated fibres and the adaxonal Schwann cell cytoplasm. This is the one
    structural lesion of ciguatera that has been seen in patients: sural nerve
    biopsies in severe cases show adaxonal Schwann cell oedema with axonal
    compression and vesicular myelin degeneration, and skin biopsy months after
    poisoning has shown diffuse axonal swellings with preserved intraepidermal
    fibre density.
  cell_types:
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  downstream:
  - target: Perioral and distal paresthesia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Structural disturbance at the node accompanies the abnormal sensation,
      although the quantitative contribution of swelling relative to ectopic
      firing has not been separated in patients.
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This was confirmed by a biopsy of the sural nerve, which revealed a striking edema in the adaxonal layer of the Schwann cell cytoplasm, with axonal compression and vesicular degeneration of the myelin."
    explanation: Human tissue evidence for the adaxonal Schwann cell oedema this node asserts.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Motor nerve terminals and perisynaptic Schwann cell soma of frog neuromuscular junctions (NMJs) exposed to CTXs were also swollen"
    explanation: >-
      Analogous swelling in a directly exposed preparation, where the human
      biopsies are observational. Note this is the perisynaptic Schwann cell at
      the neuromuscular junction, a different cell population from the adaxonal
      myelinating Schwann cell this node is about.
- name: Calcium-Dependent CGRP Release and Neurogenic Inflammation
  biological_scale: CELLULAR
  description: >-
    Depolarised sensory terminals release calcitonin gene-related peptide in a
    manner dependent on extracellular sodium and calcium and independent of
    thermosensory transient receptor potential channel activation. Nav1.9 alone,
    and Nav1.7 with Nav1.1 together, carry most of the release. Intradermal
    ciguatoxin in human volunteers produces a long-lasting painful axon reflex
    flare, which is the neurogenic-inflammation readout of this step, and CGRP
    signalling is the plausible route from afferent firing to itch.
  biological_processes:
  - preferred_term: CGRP release from sensory nerve terminals
    modifier: INCREASED
    term:
      id: GO:0007269
      label: neurotransmitter secretion
  cell_types:
  - preferred_term: peptidergic CGRP-expressing sensory neuron
    term:
      id: CL:4033176
      label: dorsal root ganglion CGRP neuron
  downstream:
  - target: Hyperhidrosis
    causal_link_type: DIRECT
    description: >-
      Sweating follows the cutaneous axon reflex rather than the enteric branch:
      intracutaneous ciguatoxin in human volunteers elicits axon reflex sweating
      through efferent cholinergic sympathetic skin nerves.
    evidence:
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "In human volunteers, intracutaneous injection of low nanomolar concentrations of P-CTX-1 in the forearm elicited a striking axon reflex sweating"
      explanation: The human experiment that places sweating on the cutaneous axon-reflex route.
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "This reflects the stimulation of efferent cholinergic sympathetic skin nerves"
      explanation: Names the efferent limb of that reflex, which is the mechanism this edge asserts.
  - target: Pruritus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      CGRP-dependent neurogenic signalling is the proposed route to the itch
      that is one of the three characteristic sensory signs.
    evidence:
    - reference: PMID:28867800
      reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera"
      explanation: >-
        The authors' own statement of the link from CGRP release to itch. It is
        an interpretive step rather than a measured one in patients, which is why
        this edge is marked as having known intermediates rather than being direct.
  evidence:
  - reference: PMID:28867800
    reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels."
    explanation: Establishes the ionic dependence of the release, which is what makes it downstream of the channel lesion.
  - reference: PMID:28867800
    reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals"
    explanation: >-
      The human experimental result behind the axon reflex flare in this
      description, and the only human experimental observation in this entry.
      Graded HUMAN_CLINICAL because the quoted work was done in human subjects,
      with quote_role BACKGROUND because this paper is reporting its own earlier
      study rather than the experiment it goes on to describe.
- name: Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents
  biological_scale: CELLULAR
  description: >-
    Ciguatoxin confers cold sensitivity on a subpopulation of normally
    cold-insensitive afferents that co-express Nav1.8 and TRPA1, so innocuous
    cooling drives a nociceptive response. In spinal recordings, cold
    hypersensitivity is abolished by a Nav1.8 antagonist, only partially
    prevented by a TRPA1 antagonist, and unaffected by a TRPM8 antagonist -
    which places the lesion on the Nav1.8/TRPA1 population rather than on the
    canonical cold receptor.
  biological_processes:
  - preferred_term: detection of temperature stimulus involved in sensory perception of pain
    modifier: ABNORMAL
    term:
      id: GO:0050965
      label: detection of temperature stimulus involved in sensory perception of pain
  cell_types:
  - preferred_term: Nav1.8/TRPA1-positive primary afferent neuron
    term:
      id: CL:0000101
      label: sensory neuron
  notes: >-
    `cell_types` stays on the generic `CL:0000101` deliberately. CL was searched
    for a Nav1.8- or TRPA1-defined afferent class and has neither: its
    channel-marker neuron types are the segment-specific transcriptomic series
    (`CL:4079002` cervical dorsal root ganglion Nav1.7 neuron and its lumbar,
    sacral and thoracic siblings), which name a different channel and add a
    spinal level this claim does not make. The sibling node for CGRP release
    does get a specific term, `CL:4033176`, because CL carries a
    level-independent class there; no such class exists for Nav1.8 or TRPA1.
  downstream:
  - target: Cold allodynia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26454262
      reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav 1.8/TRPA1-positive primary afferents, which could underlie the cold allodynia reported in ciguatera."
      explanation: The authors' explicit mapping of this cellular mechanism onto the human sign.
  evidence:
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Subcutaneous injection of 10 nm ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling."
    explanation: The primary measurement - cooling responses increase after local ciguatoxin.
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both mechanical and cold hypersensitivity were completely prevented by co-injection with the Nav 1.8 antagonist A803467, whereas the transient receptor potential ankyrin 1 (TRPA1) antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to noxious cooling."
    explanation: The pharmacological dissection that assigns the effect to Nav1.8 and TRPA1.
- name: Enteric and Autonomic Neuron Hyperexcitability
  biological_scale: TISSUE
  description: >-
    Sodium channel activation in enteric and autonomic neurons produces the
    earliest and most consistent phase of the illness - nausea, vomiting,
    watery diarrhoea and abdominal cramping beginning within hours of the meal -
    together with autonomic signs such as profuse sweating and hypersalivation.
    This phase is self-limited over one to a few days while the neurological
    phase continues.
  cell_types:
  - preferred_term: enteric neuron
    term:
      id: CL:0007011
      label: enteric neuron
  biological_processes:
  - preferred_term: action potential
    modifier: INCREASED
    term:
      id: GO:0001508
      label: action potential
  downstream:
  - target: Nausea
    causal_link_type: DIRECT
  - target: Vomiting
    causal_link_type: DIRECT
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Abdominal pain
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Gastrointestinal disorders include nausea, vomiting, abdominal pain and diarrhea (watery stools)."
    explanation: Names the gastrointestinal features this node produces.
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."
    explanation: >-
      Ties the visceral pain component specifically to sodium channel activation.
      It covers abdominal pain only; the emetic, secretory and autonomic claims
      in this node rest on the enteric-plexus evidence below and on the clinical
      description above.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "In mice experimentally intoxicated with a single dose of CTX, non-myelinated nerves of the enteric nervous system (the myenteric Auerbach plexus and submucosal Meissner plexus) were swollen, as were synapses in the myenteric plexus and vas deferens smooth muscle layers."
    explanation: >-
      Direct evidence that the enteric nervous system is a substrate of the
      toxin, which is the mechanistic claim this node makes and the one the
      symptom lists above do not establish.
- name: Cardiac Conduction and Vasomotor Disturbance
  biological_scale: TISSUE
  description: >-
    How ciguatoxin slows the heart is contested, and both positions are recorded
    below. The clinical literature argues an indirect route: stimulation of
    unmyelinated vagal cardiac afferents inhibiting central vasomotor centres, so
    sympathetic output and peripheral resistance fall. Mouse histology argues a
    direct one: cardiac myocytes swell in a pattern read as myocardial sodium
    channel activation rather than as an action on cardiac autonomic nerves.
    Either route, combined with hypovolaemia from gastrointestinal losses,
    produces bradycardia, hypotension and conduction disorders. These are the
    least frequent features but the ones that make the illness life-threatening.
    They do respond to atropine, fluids and dopamine, but reversal can require
    unusually large or prolonged atropine dosing - 45 mg and 30 mg over 48 hours
    in the two published cases cited here.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  notes: >-
    `cell_types` binds the cardiac muscle cell for the direct-myocyte position
    only, which is the mouse-histology side of the controversy this node
    records. The competing clinical account places the lesion on cardiac
    autonomic nerves rather than on the myocyte, and CL has no term for the
    unmyelinated vagal cardiac afferent that account names, so only one side of
    the dispute is bindable here.
  biological_processes:
  - preferred_term: membrane depolarization
    modifier: INCREASED
    term:
      id: GO:0051899
      label: membrane depolarization
  downstream:
  - target: Bradycardia
    causal_link_type: DIRECT
  - target: Hypotension
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two patients with persistent bradycardia and hypotension after eating mackerel fish."
    explanation: Direct clinical observation of the cardiovascular phenotype this node produces.
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bradycardia and hypotension, which can be life-threatening, are common."
    explanation: Supports the severity claim in this description from a territory-wide case series.
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ciguatoxin stimulates the unmyelinated afferent cardiac branches of the vagus nerve which leads to a tonic inhibition of central vasomotor centers with reduced sympathetic output and peripheral vascular resistance, causing bradycardia, continued hypotension, and peripheral vasodilatation."
    explanation: Spells out the vagal-afferent and central-vasomotor route this node records.
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ciguatoxin action on the human heart thus appears to be related primarily to indirect effects on intrinsic nerves, rather than a direct effect on myocardial cells."
    explanation: >-
      The indirect position as the authors' conclusion, and an explicit argument
      against the myocyte being the substrate.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "A swelling of cardiac myocytes was also present, likely resulting from a direct effect (activation of the myocardial Nav channels) instead of an indirect action through activation of Nav in cardiac autonomic nerves."
    explanation: >-
      The competing direct-myocyte position. Recorded as REFUTE against the
      indirect account quoted immediately above, because the two make opposite
      claims about where the lesion sits and neither is settled.
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large doses of atropine and dopamine are needed to revert the symptoms."
    explanation: >-
      Source of the atropine-dosing claim in this description. The bradycardia is
      reversible, but in the two reported cases reversal took 45 mg and 30 mg of
      atropine over 48 hours.
phenotypes:
- category: Gastrointestinal
  name: Nausea
  frequency: VERY_FREQUENT
  description: >-
    Part of the early gastrointestinal syndrome, typically beginning within one
    to six hours of the contaminated meal.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
    temporality: ACUTE
  evidence:
  - reference: PMID:36006197
    reference_title: "Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute features consisted in general (91%; mainly, myalgia pruritus, and asthenia), gastrointestinal (90%; mainly diarrhea, abdominal pain, and nausea), neurological (72%; mainly, paresthesia, dysgeusia, and impairment of hot/cold feeling), and cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders)."
    explanation: Names nausea among the dominant gastrointestinal features, present in 90% of a 149-patient series.
- category: Gastrointestinal
  name: Vomiting
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: ACUTE
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal manifestations (i.e., diarrhea, vomiting, nausea, and abdominal pain) usually occur first, sometimes accompanied by cardiovascular disorders, mostly bradycardia and hypotension."
    explanation: Names vomiting among the first-appearing gastrointestinal manifestations.
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."
    explanation: >-
      Source of the VERY_FREQUENT grading: the gastrointestinal syndrome this
      phenotype belongs to was present in 93.9% of 234 cases.
- category: Gastrointestinal
  name: Diarrhea
  frequency: VERY_FREQUENT
  description: Watery stools, typically resolving within one to a few days.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: ACUTE
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Gastrointestinal disorders include nausea, vomiting, abdominal pain and diarrhea (watery stools)."
    explanation: Names watery diarrhoea specifically.
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."
    explanation: >-
      Source of the VERY_FREQUENT grading: the gastrointestinal syndrome this
      phenotype belongs to was present in 93.9% of 234 cases.
- category: Gastrointestinal
  name: Abdominal pain
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: ACUTE
  evidence:
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."
    explanation: >-
      Quantifies the gastrointestinal syndrome this phenotype belongs to at 93.9%
      of 234 cases, which is the basis for the VERY_FREQUENT grading across the
      gastrointestinal block.
- category: Neurological
  name: Perioral and distal paresthesia
  frequency: FREQUENT
  description: >-
    Tingling that begins around the mouth - lips and tongue - and then involves
    the extremities. With cold allodynia and pruritus it is one of the three
    sensory signs that make the clinical diagnosis.
  phenotype_term:
    preferred_term: Perioral and distal paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neurological symptoms begin with early paresthesia on the face and especially around the mouth (lips, tongue), then rather involve the extremities."
    explanation: States the perioral-then-distal distribution this phenotype records.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Among the sensory disturbances, in most cases, three particular signs are characteristic: paresthesia, cold dysesthesia and pruritus."
    explanation: >-
      Supports the diagnostic-triad claim, and is the basis for the FREQUENT
      grading - "in most cases" is a majority statement, not the 80% the
      VERY_FREQUENT band requires.
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."
    explanation: >-
      Puts a number on it: neurological signs in 76.0% of 234 cases, with
      paresthesia named first.
- category: Neurological
  name: Cold allodynia
  frequency: VERY_FREQUENT
  description: >-
    The near-pathognomonic sign. Innocuous cool contact is felt as intense
    burning pain. It is often described as a reversal of hot and cold sensation,
    but burning pain on exposure to cold is the more accurate description. It
    appears mostly within the first two days.
  phenotype_term:
    preferred_term: cold allodynia
    term:
      id: HP:0012533
      label: Allodynia
  diagnostic: true
  notes: >-
    HPO has no cold-specific allodynia term - a search of HP labels returns
    `HP:0012533` Allodynia, `HP:0012534` Dysesthesia and `HP:0010829` Impaired
    temperature sensation, none of which names cold-evoked pain. Allodynia is
    bound because the defining feature is pain from a normally non-painful
    stimulus, and the cold qualifier is carried in `preferred_term` rather than
    manufactured as a narrower ontology match.
  evidence:
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold."
    explanation: Source of both the phenomenology and the correction to the temperature-reversal wording.
  - reference: PMID:28867800
    reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "temperature dysesthesia, or cold allodynia, a pathophysiological condition where innocuous cold is perceived as painful burning of the skin, is considered pathognomonic and occurs in up to 95% of ciguatera sufferers."
    explanation: Supports both the pathognomonic status and the VERY_FREQUENT grading.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Painful sensations on contact with cold (cold dysesthesia) appear mostly within the first 2 days."
    explanation: Establishes the timing stated in this description.
- category: Neurological
  name: Pruritus
  frequency: VERY_FREQUENT
  description: >-
    Itch beginning one to two days after the meal, sometimes with a rash, and
    characteristically exacerbated by alcohol. It is one of the three
    characteristic sensory signs and one of the most persistent.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pruritus (itch), which is a very common symptom, begins 1 to 2 days after the ciguateric meal, sometimes associated with a skin rash."
    explanation: States the frequency, the latency and the rash association recorded here.
- category: Neurological
  name: Hyperesthesia
  description: >-
    Superficial hyperesthesia with sensations of burning and electric
    discharges, distinct from the cold-evoked pain recorded separately.
  phenotype_term:
    preferred_term: Hyperesthesia
    term:
      id: HP:0100963
      label: Hyperesthesia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "superficial hyperesthesia with sensations of burning and electric discharges"
    explanation: Names the sign and the qualities this description records.
- category: Musculoskeletal
  name: Myalgia
  frequency: FREQUENT
  description: Muscle pain, reported especially in the legs.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Myalgia, especially in the muscles of the legs, is also frequently reported, as well as other sensory disorders, including a metallic taste"
    explanation: States the myalgia and its leg predominance.
- category: Musculoskeletal
  name: Arthralgia
  description: Joint pain, mainly affecting large joints - knees, ankles, shoulders and elbows.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "arthralgia mainly affecting the large joints (knees, ankles, shoulders and elbows)"
    explanation: States the joint distribution recorded here.
- category: Neurological
  name: Parageusia
  description: A metallic or otherwise distorted taste, reported among the sensory disturbances.
  phenotype_term:
    preferred_term: metallic taste
    term:
      id: HP:0031249
      label: Parageusia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Myalgia, especially in the muscles of the legs, is also frequently reported, as well as other sensory disorders, including a metallic taste"
    explanation: Names metallic taste among the reported sensory disorders.
- category: Neurological
  name: Headache
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:28867800
    reference_title: "Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes Na(V)1.9, Na(V)1.7 and Na(V)1.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "distressing, often persistent sensory disturbances such as perioral and distal paresthesias, dysesthesias, pruritus, headache, asthenia, myalgia, arthralgia and tooth pain"
    explanation: Lists headache among the reported symptoms.
- category: Neuromuscular
  name: Muscle weakness
  frequency: FREQUENT
  description: Motor complaints including muscle weakness and general asthenia.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Motor disorders, including muscle weakness and general asthenia, are common complaints"
    explanation: States that motor weakness is a common complaint.
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  description: >-
    Asthenia in the acute phase and tenacious fatigue in the chronic phase,
    where it is one of the dominant persisting complaints.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mostly under the traits of neurological and psychiatric disorders (i.e., tenacious fatigue, paraesthesia, dysesthesia, pruritus, attention deficit disorder, anxiety, depression)"
    explanation: Names fatigue first among the persisting manifestations.
- category: Autonomic
  name: Hyperhidrosis
  description: Profuse sweating, reported with hypersalivation as an autonomic sign.
  phenotype_term:
    preferred_term: profuse sweating
    term:
      id: HP:0000975
      label: Hyperhidrosis
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Autonomic signs, including profuse sweating or hypersalivation, are also often described."
    explanation: Names profuse sweating as an autonomic sign of the illness.
- category: Cardiovascular
  name: Bradycardia
  frequency: FREQUENT
  description: >-
    Sinus bradycardia, sometimes persistent enough to need large cumulative
    atropine doses over days. Cardiovascular signs were present in 22% of a
    Martinique series and 40.3% of a Guadeloupe series, so the frequency is real
    but region- and ascertainment-dependent; the FREQUENT grading follows the
    higher of the two.
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although cardiovascular symptoms are rare with ciguatoxin, we report two cases with bradycardia and hypotension."
    explanation: Direct case documentation of the sign, and of its relative rarity.
  - reference: PMID:36006197
    reference_title: "Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders)"
    explanation: Source of the 22% figure quoted in this description.
- category: Cardiovascular
  name: Hypotension
  frequency: FREQUENT
  description: >-
    Reported with bradycardia as part of the cardiovascular syndrome, in 22% of
    a Martinique series and the 40.3% of a Guadeloupe series with any
    cardiovascular sign.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bradycardia and hypotension, which can be life-threatening, are common."
    explanation: >-
      Establishes hypotension as a recognised and potentially fatal feature, and
      as common - the basis for the FREQUENT grading.
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.9% of patients experienced gastrointestinal symptoms, 76.0% presented neurological signs (mainly paresthesia, dysesthesia and pruritus) and 40.3% presented cardiovascular symptoms (bradycardia and/or hypotension)."
    explanation: Puts a number on the cardiovascular syndrome this phenotype belongs to.
- category: Neurological
  name: Ataxia
  description: >-
    Impaired motor coordination, in some cases severe enough that the patient
    cannot stand or walk. Reported among the less common neurological signs,
    with no frequency given in any source cited here.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."
    explanation: Names impaired motor coordination and ataxia among the neurological signs.
- category: Neurological
  name: Hyporeflexia
  description: Reduction or abolition of the deep tendon reflexes.
  phenotype_term:
    preferred_term: reduction or abolition of deep tendon reflexes
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."
    explanation: >-
      Names the reflex change. `HP:0001265` Hyporeflexia covers the reduction;
      the abolition the same sentence reports would be areflexia
      (`HP:0001284`), and the source gives no basis for splitting the two, so
      the reduced-reflex term is bound and the fuller phrase kept in
      `preferred_term`.
- category: Neurological
  name: Vertigo
  description: >-
    Reported among the neurological signs. Left unconnected in the pathograph:
    no source cited here traces it to the peripheral afferent mechanism this
    entry models, and a vestibular route would be a different claim.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These include vertigo, visual and/or oculomotor disturbances, reduction or abolition of deep tendon reflexes, paresis and impaired motor coordination, with some cases developing an inability to stand or walk (ataxia)."
    explanation: Names vertigo first among these neurological signs.
- category: Genitourinary
  name: Dysuria
  description: Painful micturition, reported with other urogenital pain.
  phenotype_term:
    preferred_term: painful micturition
    term:
      id: HP:0100518
      label: Dysuria
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "dental pain, headaches, painful micturition and other urogenital pain"
    explanation: >-
      Names painful micturition among the sensory disturbances. The same
      sentence names dental pain, which is not added as a phenotype because HPO
      has no tooth-pain term - a label search returns only `HP:0005216` Impaired
      mastication, which denotes something else.
progression:
- phase: Acute gastrointestinal phase
  duration: 1-2 days
  duration_days: "2"
  incubation_days: "1"
  notes: >-
    Onset is a few minutes to 24 hours after the meal, and falls between one and
    six hours in 90% of cases. `incubation_days: 1` is the coarse
    day-granularity encoding of that sub-day latency; the verbatim range is in
    the evidence below.
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The first symptoms appear a few minutes to 24 h after the toxic fish meal, but occur between 1 and 6 h in 90% of cases"
    explanation: Establishes the latency of this phase.
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The gastrointestinal effects are typically transient (1–5 days), whereas neurological symptoms can persist for weeks to many months"
    explanation: Establishes that this phase is transient and separates it from the neurological one.
- phase: Acute neurological and cardiovascular phase
  duration: days to weeks
  notes: >-
    Overlaps with or shortly follows the gastrointestinal phase. Sensory
    disturbance dominates; cardiovascular signs when present appear in the first
    day.
  evidence:
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In affected subjects, the gastrointestinal symptoms often subside within days, whereas the neurological symptoms can persist for weeks or even months."
    explanation: Contrasts the duration of this phase with the preceding one.
- phase: Chronic ciguatera
  duration: 3 months or longer
  notes: >-
    Defined in the literature as symptoms lasting three months or more, affecting
    at least a fifth of patients. Manifestations are mainly neurological and
    psychiatric - tenacious fatigue, paresthesia, dysesthesia, pruritus, anxiety
    and depression - and may be continuous or appear as reactivation peaks
    triggered by marine or fresh-water foods, alcohol, nuts or red meat.
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic forms of CP with symptoms lasting ≥3 months are a real clinical challenge."
    explanation: Establishes the three-month definition this phase uses.
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"
    explanation: Quantifies how many patients reach this phase.
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ciguatera poisoning is a globally occurring seafood disease caused by the ingestion of marine
      products contaminated with dinoflagellate produced neurotoxins. ... Among all studied
      variables, five significant predictors of having symptoms lasting ≥3 months were identified:
      age, tobacco consumption, acute bradycardia, laboratory measures of urea, and neutrophils. ...
      Chronic forms of CP with symptoms lasting ≥3 months are a real clinical challenge. Even though
      chronic CP cases are regularly reported, studies dedicated to the understanding of this
      phenomenon are scarce, especially due to the lack of a clear consensus regarding its clinical
      definition. Indeed, some CP manifestations may persist for months or even years after the
      initial poisoning, mostly under the traits of neurological and psychiatric disorders (i.e.,
      tenacious fatigue, paraesthesia, dysesthesia, pruritus, attention deficit disorder, anxiety,
      depression) ... These manifestations can be expressed continuously or through transient
      reactivation peaks, triggered by multiple factors (e.g., consumption of marine/fresh
      water-related products, even from non-endemic region, alcohol, nuts, and red meat. ...
      Considering that at least 20% of the persons affected by CP are likely to develop a persistent
      form
    explanation: >-
      Connects the chronic ciguatera duration studied in the hospitalized cohort to the paper’s
      reviewed background on persistent manifestations, reactivation triggers and frequency. The
      background estimate is not a new prevalence measurement from the 49-patient cohort.
prevalence:
- population: Hong Kong, 1989-2008
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.02
  rate_low: 0.33
  rate_high: 6.49
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    Reported as 3.3-64.9 per million per year, median 10.2 per million;
    normalised here by dividing by ten. The band reflects the median, 1.02 per
    100,000 per year.
  evidence:
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From 1989 to 2008, the annual incidence of ciguatera varied between 3.3 and 64.9 (median 10.2) per million people."
    explanation: Source of the rate and its range.
- population: Guadeloupe, French West Indies, 2013-2016
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 14.7
  rate_low: 12.9
  rate_high: 16.6
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    Reported as a mean annual incidence of 1.47 per 10,000 with a 95% confidence
    interval of 1.29-1.66, about five times the incidence reported for the same
    territory in 1996-2006.
  evidence:
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two hundred and thirty-four cases of poisoning were observed, with a mean annual incidence of 1.47/10,000"
    explanation: Source of the rate and the case count behind it.
- population: Martinique, French West Indies, 2012-2018
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 6.7
  rate_denominator: PERSON_YEARS
  notes: >-
    Reported as 0.67 cases per 10,000 patient-years. The denominator is
    person-time as published, not population-per-year, so it is not directly
    comparable with the Guadeloupe figure above despite the neighbouring
    geography.
  evidence:
  - reference: PMID:36006197
    reference_title: "Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CP incidence was 0.67 cases per 10,000 patient-years in Martinique over the study period."
    explanation: Source of the rate and its stated denominator.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Global burden is quoted as tens of thousands of cases per year, but as an
    absolute count with no denominator, so it is recorded here as a literature
    case count rather than as a rate. Every source that gives a figure also says
    it is a substantial underestimate.
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this would affect 10,000 to 50,000 persons every year"
    explanation: One of the commonly quoted global burden figures.
  - reference: PMID:41610130
    reference_title: "Risk of ciguatoxins is shaped by Gambierdiscus community structure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When CTXs accumulate in seafood they cause Ciguatera Poisoning (CP), which affects ca. 20-50,000 people p.a. and is likely worsened by climate change."
    explanation: >-
      An independent estimate in the same order of magnitude. Graded OTHER, as
      the same sentence is graded on the climate link it also carries; the
      quoted sentence is a marine-science paper's framing rather than a clinical
      series.
diagnosis:
- name: Clinical diagnosis from exposure history and syndrome
  description: >-
    There is no confirmatory bedside test. The diagnosis rests on a recent
    reef-fish meal plus the characteristic sequence - gastrointestinal upset
    followed by paresthesia, cold allodynia and pruritus - in a non-febrile
    patient, supported where possible by analytical testing of a remnant of the
    fish that was eaten.
  evidence:
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of CFP is based on the recent fish-eating history of the patient(s), clinical presentation, and whenever possible, results from analytical testing of a remnant of the fish consumed by the person(s) suffering from CFP."
    explanation: States all three legs of the diagnosis this entry records.
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients diagnosed with CFP without fish testing confirmation should be warned about the uncertainty of a purely clinical diagnosis and recommended for additional medical evaluation if symptoms recur or do not resolve."
    explanation: Records how uncertain a clinical-only diagnosis is held to be, which is why fish testing matters.
- name: Absence of a human biomarker of ciguatoxin exposure
  presence: absent
  description: >-
    The gap that shapes everything else about diagnosing this disease. Nothing
    measurable in the patient confirms exposure, so every assay below is applied
    to the fish rather than to the person, and the clinical diagnosis cannot be
    laboratory-confirmed in the patient at all.
  evidence:
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "There are currently no identified biomarkers that can be used to confirm exposure to CTX in humans"
    explanation: States the absence directly.
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The development of methods to confirm exposure to CTX in affected humans will assist not only in the diagnostic process, but also in the validity of clinical trials investigating treatments for individuals with a presumed CFP diagnosis."
    explanation: >-
      Names the downstream consequence that matters for this entry - it is also
      why the treatment evidence recorded here is as weak as it is.
- name: Ciguatoxin detection in the implicated fish
  description: >-
    The analytical work is done on fish tissue. The FDA protocol is a two-tier
    screen-then-confirm design: an N2a mouse neuroblastoma cell assay for
    activity consistent with the ciguatoxin mode of action, then LC-MS/MS for
    molecular confirmation. Receptor-binding assays and ELISA are the main
    alternatives, and the historical mouse bioassay is being displaced on
    welfare and specificity grounds.
  evidence:
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "in vitro mouse neuroblastoma (N2a) cell assay as a semi-quantitative screen for toxicity consistent with CTX mode of action; and (2) liquid chromatography tandem-mass spectrometry (LC-MS/MS) for molecular confirmation of CTX."
    explanation: The two tiers of the regulatory protocol this diagnosis entry describes.
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Alternative methods for CTX detection in fish include receptor binding assays"
    explanation: Names the alternative assay class recorded here.
  - reference: PMID:18623118
    reference_title: "Detection of ciguatoxin in fish tissue using sandwich ELISA and neuroblastoma cell bioassay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The applicability of a new enzyme-linked immunoassay (ELISA) for detecting ciguatoxin (CTX) in fish tissue was evaluated by testing three fish species commonly implicated in ciguatera fish poisoning in Hawaii."
    explanation: A worked example of the ELISA route, applied to fish tissue rather than to a patient.
differential_diagnoses:
- name: Other marine and fish-borne toxin syndromes
  description: >-
    Ciguatera shares symptoms with paralytic, neurotoxic and diarrhetic
    shellfish poisoning, scombrotoxin (histamine) fish poisoning, pufferfish
    tetrodotoxin poisoning and hallucinatory fish poisoning. All arrive through
    the same "I ate seafood and got sick" history, so the exposure story does not
    discriminate between them.
  distinguishing_features:
  - >-
    Cold allodynia - burning pain on innocuous cold contact - is the
    discriminating feature, and is described as pathognomonic for ciguatera.
  - >-
    The implicated species differs: ciguatera follows carnivorous reef fish
    (jacks, groupers, snappers, barracuda, moray eels, amberjack).
  notes: >-
    Deliberately short. The features that separate ciguatera from each named
    alternative individually - the histamine mechanism of scombroid, the
    ascending paralysis of tetrodotoxin - are standard clinical teaching but are
    not stated by any reference cited in this entry, so they are omitted rather
    than asserted without a source. Adding them means citing a source that makes
    each comparison.
  evidence:
  - reference: PMID:28335428
    reference_title: "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CFP induces some symptoms in common with paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), scombrotoxin fish poisoning, pufferfish poisoning (also referred to as Fugu poisoning), and hallucinatory fish poisoning"
    explanation: Names the differential this entry records.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold."
    explanation: >-
      Supports cold allodynia as the discriminating feature. Its specificity
      against the other syndromes named here is not quantified in any source
      cited by this entry, so "near-pathognomonic" is the clinical consensus
      rather than a measured test characteristic.
histopathology:
- name: Adaxonal Schwann cell oedema with axonal compression on sural nerve biopsy
  description: >-
    The one structural lesion of ciguatera documented in human tissue. Sural
    nerve biopsy in severe cases shows striking oedema of the adaxonal layer of
    the Schwann cell cytoplasm, compressing the axon, with vesicular
    degeneration of the myelin.
  diagnostic: false
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This was confirmed by a biopsy of the sural nerve, which revealed a striking edema in the adaxonal layer of the Schwann cell cytoplasm, with axonal compression and vesicular degeneration of the myelin."
    explanation: Describes the finding exactly as recorded here.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In two severe cases, edema of myelin fibers, sometimes intra-axonal, or of the adaxonal Schwann cell cytoplasm, were revealed in biopsied sural nerves"
    explanation: >-
      Establishes how few cases this rests on - two - which is why it is recorded
      as a finding rather than as a diagnostic criterion.
  notes: >-
    No `finding_term` is bound. HPO's nearest terms describe peripheral
    myelination abnormality (`HP:0003130`) and onion bulb formation
    (`HP:0003383`), neither of which denotes adaxonal Schwann cell oedema, and
    binding a broader myelination term would assert a different lesion. The
    finding is carried as prose and as the `Nodal and Adaxonal Schwann Cell
    Swelling` pathophysiology node instead.
- name: Diffuse axonal swellings with preserved intraepidermal nerve fibre density on skin biopsy
  description: >-
    Skin biopsy of the distal leg two months after intoxication shows diffuse
    axonal swellings while the density of intraepidermal nerve fibres remains
    normal. The combination matters: it argues that the persisting sensory
    disturbance is a functional and structural change in surviving fibres rather
    than a small-fibre neuropathy with fibre loss.
  diagnostic: false
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A skin biopsy from the distal leg, carried out 2 months after intoxication, revealed that the density of the intraepidermal nerve fibers was normal, but diffuse axonal swellings were observed"
    explanation: >-
      States both halves of the finding - swelling present, fibre density
      preserved - which is the whole of the inference drawn here.
environmental:
- name: Consumption of ciguatoxin-contaminated carnivorous reef fish
  description: >-
    The sole route of exposure. Carnivorous reef predators - jacks and trevallies,
    snappers, groupers, barracuda, moray eels, amberjack and king mackerel -
    carry the highest toxin burden because the toxin biomagnifies up the reef
    food chain, and liver, roe and viscera concentrate it further. Contaminated
    fish are indistinguishable from safe ones by taste, smell or appearance, and
    the toxins survive cooking, salting and freezing, so no consumer-level
    precaution short of avoiding the species removes the risk.
  exposure_term:
    preferred_term: dietary exposure to ciguatoxin in contaminated reef fish
    term:
      id: ECTO:0000537
      label: exposure to toxin
  food_source:
    preferred_term: sea water fish food product
    term:
      id: FOODON:00001055
      label: sea water fish food product
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: ACUTE
  influences_mechanisms:
  - target: Ingestion and Systemic Distribution of Ciguatoxin
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The meal is what delivers the toxin the whole entry follows from.
    evidence:
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs)."
      explanation: States consumption of contaminated fish as the cause of the disease.
  notes: >-
    Bound to `ECTO:0000537` exposure to toxin. ECTO was searched through this
    repository's adapter (`sqlite:obo:ecto`) for a ciguatoxin or ciguatera
    exposure class and none exists. The nearest classes under `ECTO:0000537` are
    mycotoxin, phytoalexin, phytotoxin, nephrotoxin, uremic toxin and virulence
    factor, and the fish-ingestion classes that do exist (`ECTO:0070099`
    bluefish, `ECTO:0070100` swordfish, `ECTO:0070189` whitefish,
    `ECTO:0070209` dark fish flesh) name unrelated species. One algal-toxin
    class does exist outside that subtree - `ECTO:8000033` exposure to
    accumulation of toxins from algal bloom process, whose parent is
    `ECTO:8000000` exposure to environmental process, so a descendant walk from
    `ECTO:0000537` misses it. It was considered and not used: ciguatoxin reaches
    people through years of food-chain accumulation in fish, not through a bloom
    event, and this entry's exposure is a meal rather than an environmental
    process. The
    specific agent is carried in `preferred_term`, and the toxin itself is bound
    to `CHEBI:61275` on the pathophysiology nodes where it acts. `food_source`
    names the marine fish product class rather than a species, because the
    implicated species differ by ocean basin and the slot takes a single term.
  evidence:
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels."
    explanation: Names the implicated species and the undetectability that this description rests on.
  - reference: PMID:36006197
    reference_title: "Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CP was mainly attributed to the ingestion of trevallies (59%), snappers (13%), and king mackerels (8%)"
    explanation: >-
      Quantifies which species actually caused disease in one Caribbean series,
      which is a stronger claim than a list of high-risk species.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ciguateric fish are indistinguishable from uncontaminated ones with regard to taste, smell, and appearance."
    explanation: Supports the claim that no consumer-level inspection detects the exposure.
- name: Sea surface warming and coral reef disturbance
  description: >-
    Reef degradation and rising sea surface temperatures expand the algal
    substrate that Gambierdiscus and Fukuyoa colonise and extend the geographic
    range in which ciguatera occurs, including into previously unaffected
    temperate-adjacent waters. This acts on the upstream production step rather
    than on the human host.
  exposure_term:
    preferred_term: exposure to elevated sea surface temperature and degraded coral reef habitat
  influences_mechanisms:
  - target: Gambierdiscus Ciguatoxin Production on Reef Substrate
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Warming and reef disturbance change where and how much toxin-producing
      dinoflagellate is present, which sets regional risk rather than causing an
      individual poisoning.
    evidence:
    - reference: PMID:41610130
      reference_title: "Risk of ciguatoxins is shaped by Gambierdiscus community structure."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "When CTXs accumulate in seafood they cause Ciguatera Poisoning (CP), which affects ca. 20-50,000 people p.a. and is likely worsened by climate change."
      explanation: States climate change as a worsening factor for the disease, which is this link.
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "global warming has tended to extend the areas concerned"
      explanation: >-
        States the geographic consequence directly - warming extends where the
        disease occurs, which is what this PREDISPOSES link asserts.
  notes: >-
    `exposure_term` deliberately carries a free-text `preferred_term` with no
    `term:`. ECTO was searched for a sea-surface-temperature, ocean-warming or
    reef-degradation exposure class and none exists; the temperature classes
    available describe exposure of an organism to ambient heat, which is not the
    claim here - the warming acts on the dinoflagellate habitat, not on the
    patient. `ECTO:0000537` would be wrong for the same reason, since no toxin
    is being described at this step.
  evidence:
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "global warming has tended to extend the areas concerned"
    explanation: States the range-expansion claim in this description.
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "oceans warm and algal blooms become more frequent, ciguatera is now emerging as a significant issue in Asia, America and parts of Europe"
    explanation: >-
      Ties ocean warming and bloom frequency directly to the geographic expansion
      this exposure describes, rather than the expansion alone.
  - reference: PMID:29449664
    reference_title: "Incidence and clinical characteristics of ciguatera fish poisoning in Guadeloupe (French West Indies) between 2013 and 2016: a retrospective cases-series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The monitoring of ciguatera poisoning throughout the Caribbean region must be improved, notably after reef disturbance due to Irma and Maria major cyclones."
    explanation: >-
      A surveillance recommendation, not a measurement. It is included because it
      shows investigators treating named cyclone reef disturbance as a reason to
      expect changed ciguatera risk, which is weaker than demonstrating it.
treatments:
- name: Supportive and symptomatic care
  description: >-
    First-line and the only universally agreed management. Rehydration for
    gastrointestinal losses, antiemetics and antidiarrhoeals, analgesia for
    myalgia and arthralgia, antihistamines for pruritus, and atropine plus fluid
    and vasopressor support for bradycardia and hypotension. Rehydration also
    has to precede any mannitol infusion.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  - preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of ciguatera is primarily supportive and symptomatic."
    explanation: States supportive care as the mainstay.
  - reference: PMID:36006197
    reference_title: "Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management was supportive. No patient died but symptoms persisted in 40% of the 77 patients with follow-up at day 15."
    explanation: >-
      Records what was actually given across a 149-patient series, together with
      the outcome - no deaths, but persisting symptoms in 40% of those followed up.
  - reference: PMID:19005579
    reference_title: "Ciguatera fish poisoning: treatment, prevention and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "indicated that mannitol should not be administered until the patient is adequately rehydrated"
    explanation: Supports rehydration preceding mannitol, which is the ordering claim in this description.
- name: Intravenous mannitol
  description: >-
    The most studied specific intervention and a genuinely contested one.
    Uncontrolled case series, an unblinded comparative trial and many case
    reports describe rapid neurological improvement when mannitol is given
    early; the single randomised controlled trial found no difference from
    normal saline. The proposed mechanism - osmotic reversal of the neuronal
    oedema this entry records as nodal and adaxonal swelling - is supported in
    isolated nerve preparations but not in intact animals. Both positions are
    recorded below rather than resolved.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mannitol
      term:
        id: CHEBI:16899
        label: D-mannitol
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Nodal and Adaxonal Schwann Cell Swelling
    description: >-
      The proposed target: hyperosmolar mannitol reverses the osmotic swelling
      at the node.
    evidence:
    - reference: PMID:33066435
      reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "nodal swelling of myelinated nerve fibers was prevented by tetrodotoxin and completely prevented and reversed by pretreatment with or the addition of hyperosmolar external solutions of D-mannitol"
      explanation: Demonstrates that hyperosmolar mannitol reverses this specific lesion in nerve fibres.
    - reference: PMID:28535116
      reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Treatment with mannitol fails to correct these effects."
      explanation: >-
        The same reversal does not happen in an intact animal - in rats given
        intraperitoneal ciguatoxin, mannitol failed to correct the increased
        refractory period and slowed conduction velocity. This is why the
        treatment description says the mechanism is supported in isolated nerve
        preparations but not in intact animals.
  evidence:
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Evidence supporting mannitol for ciguatera fish poisoning includes four uncontrolled case series, one prospective, unblinded comparative trial and several case reports."
    explanation: The body of evidence favouring mannitol, and its design limitations.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In 2002, a small randomized, controlled trial reported no significant difference between mannitol and normal saline."
    explanation: >-
      The only randomised evidence, and it contradicts the claim that mannitol
      is effective. Recorded as a separate REFUTE item rather than folded into
      the supporting one, because the two quotes make opposite claims.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is reasonable to consider using intravenous mannitol in cases of acute ciguatera fish poisoning."
    explanation: The reviewers' net position after weighing both bodies of evidence.
  - reference: PMID:19005579
    reference_title: "Ciguatera fish poisoning: treatment, prevention and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The effect of mannitol infusion is thought to be mediated by the osmotic reduction of neuronal edema"
    explanation: States the proposed mechanism this treatment is linked to.
- name: Atropine for symptomatic bradycardia
  description: >-
    The specific pharmacologic intervention for the one life-threatening feature
    of the illness, given with intravenous fluids and dopamine. Reversal can need
    unusually large cumulative doses over days - 45 mg and 30 mg over 48 hours in
    the two published cases - so a persisting bradycardia is a reason to continue
    rather than to abandon it.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atropine
      term:
        id: CHEBI:16684
        label: atropine
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:25333356
    reference_title: "Epidemiology and clinical features of ciguatera fish poisoning in Hong Kong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe bradycardia and prolonged hypotension can occur, necessitating prompt treatment with intravenous atropine, intravenous fluid replacement and dopamine infusion"
    explanation: States the indication and the three-drug combination this treatment records.
  - reference: PMID:22574244
    reference_title: "Cardiovascular Complications in Ciguatera Fish Poisoning: A Wake-up Call."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A continuous infusion of atropine with a total dose of 45 mg over 48 hours was given."
    explanation: Source of the cumulative-dose figure in this description.
  - reference: PMID:33066435
    reference_title: "Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "atropine effectively relieves the gastrointestinal and cardiovascular disturbances"
    explanation: >-
      Independent statement that atropine works here, which is why this entry no
      longer describes the bradycardia as atropine-resistant.
- name: Neuropathic-pain pharmacotherapy for persistent symptoms
  description: >-
    Amitriptyline, gabapentin, pregabalin, fluoxetine, duloxetine and tocainide
    have all been reported to suppress the paresthesia, dysesthesia and pruritus
    of the chronic phase. The evidence is case reports and overlapping case
    series only, none has been shown superior to another, and a long duration of
    treatment appears necessary to maintain the benefit.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amitriptyline
      term:
        id: CHEBI:2666
        label: amitriptyline
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
    - preferred_term: pregabalin
      term:
        id: CHEBI:64356
        label: pregabalin
    - preferred_term: duloxetine
      term:
        id: CHEBI:36796
        label: duloxetine
    - preferred_term: fluoxetine
      term:
        id: CHEBI:5118
        label: fluoxetine
    - preferred_term: tocainide
      term:
        id: CHEBI:9611
        label: tocainide
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Repetitive Firing of Peripheral Sensory Afferents
    description: >-
      These are the agents used for neuropathic pain generally, and the
      persisting paresthesia and dysesthesia they suppress here are the clinical
      expression of this node. Whether they act on this mechanism in ciguatera
      specifically has not been shown.
    evidence:
    - reference: PMID:28535116
      reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases."
      explanation: >-
        States the observed effect. It supports the symptom claim; the mechanism
        attribution in this link's description is an inference and is flagged as
        such.
  target_phenotypes:
  - preferred_term: Perioral and distal paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Evidence regarding other treatments consists only of ten case reports and three overlapping case series that describe using amitriptyline, fluoxetine, duloxetine, gabapentin, pregabalin, or tocainide."
    explanation: Names the agents and states the quality of evidence behind them.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases."
    explanation: States the effect claimed for this treatment class.
  - reference: PMID:28535116
    reference_title: "Is mannitol the treatment of choice for patients with ciguatera fish poisoning?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, the human evidence is of low quality for all treatments."
    explanation: The caveat this description carries, in the reviewers' own words.
- name: Avoidance of relapse-triggering foods
  description: >-
    Patients are counselled to avoid reef fish and other marine products,
    alcohol, nuts and red meat after an episode, because these are reported to
    reactivate neurological symptoms months after the index poisoning. The
    trigger list is observational and the mechanism is unknown.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These manifestations can be expressed continuously or through transient reactivation peaks, triggered by multiple factors (e.g., consumption of marine/fresh water-related products, even from non-endemic region, alcohol, nuts, and red meat."
    explanation: Names the triggers this avoidance advice is built on.
animal_models:
- name: Cook Islands naturally occurring canine and feline ciguatera
  species: Dog
  category: Natural disease
  publication: PMID:32158145
  description: >-
    Not an engineered model. Dogs and cats in Rarotonga eat reef fish and fish
    scraps and develop ciguatera in numbers large enough to study: 246 cases in
    six years of records from the only veterinary clinic in the territory,
    165 dogs and 81 cats. The presentation is motor-dominant - ataxia, paresis
    and recumbency - rather than the sensory-dominant syndrome seen in people,
    which is the main reason this is recorded as partially recapitulating rather
    than recapitulating.
  modeled_mechanisms:
  - target: Ingestion and Systemic Distribution of Ciguatoxin
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The same exposure route and the same toxin, in a naturally exposed
      non-human population with veterinary follow-up that human series rarely
      match.
    limitations: >-
      The clinical picture diverges from the human one: motor signs dominate and
      the sensory disturbances that define human ciguatera cannot be elicited
      from an animal at all, so the syndrome is not comparable symptom by
      symptom. Dose is unmeasured and probably higher than a human meal, because
      these animals scavenge viscera and whole carcasses where the toxin
      concentrates. No toxin assay confirmed exposure in individual cases; the
      case definition is clinical.
    evidence:
    - reference: PMID:32158145
      reference_title: "A descriptive study of ciguatera fish poisoning in Cook Islands dogs and cats: Demographic, temporal, and spatial distribution of cases."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A total of 246 cases of CFP were identified, comprising 165 dogs and 81 cats."
      explanation: Establishes the scale of the naturally exposed population this model rests on.
    - reference: PMID:32848300
      reference_title: "A descriptive study of ciguatera fish poisoning in Cook Islands dogs and cats: Treatment and outcome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Prolonged periods of anorexia and recumbency were common in both species."
      explanation: Documents the recumbency named in the limitations above.
    - reference: PMID:32255982
      reference_title: "A descriptive study of ciguatera fish poisoning in Cook Islands dogs and cats: Exposure history, clinical signs, and formulation of a case definition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The toxicosis was characterized by motor dysfunction with a high frequency of ataxia and paresis/paralysis/recumbency."
      explanation: >-
        States the motor dominance directly, which is the divergence from the
        sensory-dominant human syndrome that limits this model.
  evidence:
  - reference: PMID:32848300
    reference_title: "A descriptive study of ciguatera fish poisoning in Cook Islands dogs and cats: Treatment and outcome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The survival rate was >90% and almost all mortalities occurred in the first week of hospitalization."
    explanation: >-
      Outcome data from the same population, which parallels the low human case
      fatality and supports treating the animal disease as informative.
  - reference: PMID:32848300
    reference_title: "A descriptive study of ciguatera fish poisoning in Cook Islands dogs and cats: Treatment and outcome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The treatments most commonly administered to cases were fluid therapy and muscle relaxants."
    explanation: Records that management was supportive here too, as in humans.
  notes: >-
    Recorded under a single `species: Dog` entry although the source series
    covers dogs and cats together; the slot takes one value and dogs are the
    larger group. The feline cases are described in the same papers and the
    quoted findings are reported for both species.
- name: Rat spinal dorsal horn ciguatoxin cold hypersensitivity model
  species: Rat
  category: Induced
  publication: PMID:26454262
  description: >-
    Subcutaneous Pacific ciguatoxin-2 into the receptive field of a dorsal horn
    wide-dynamic-range neuron, with in vivo electrophysiological recording of
    responses to cooling. This is the model that assigned ciguatera cold
    allodynia to Nav1.8 and TRPA1 rather than to the canonical cold receptor
    TRPM8.
  modeled_mechanisms:
  - target: Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Local ciguatoxin reproduces the cold hypersensitivity, and the channel
      dependence is established by selective antagonists.
    limitations: >-
      The readout is a spinal neuronal firing rate in a non-sentient
      preparation, not a reported sensation, so the mapping onto human cold
      allodynia is an inference the authors make explicitly rather than a
      measurement. The toxin is injected locally at a known concentration rather
      than ingested and distributed, so absorption, congener mixture and dose
      are all bypassed.
    readouts:
    - name: Dorsal horn neuronal response to innocuous and noxious cooling
      target: Cold Sensitisation of Nav1.8/TRPA1-Positive Afferents
      direction: INCREASED
      interpretation: >-
        Increased firing to cooling after local ciguatoxin is the electrophysiological
        correlate of cold allodynia.
      evidence:
      - reference: PMID:26454262
        reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Subcutaneous injection of 10 nm ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling."
        explanation: Reports the measurement and its direction.
    evidence:
    - reference: PMID:26454262
      reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav 1.8/TRPA1-positive primary afferents, which could underlie the cold allodynia reported in ciguatera."
      explanation: The authors' own statement that this model informs the human sign.
  evidence:
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study examined, for the first time, the neural substrates and molecular components of Pacific ciguatoxin-2-induced cold hypersensitivity."
    explanation: >-
      States what the preparation was built to measure, which is what makes it a
      model of this entry's cold-sensitisation node.
  - reference: PMID:26454262
    reference_title: "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non-sentient rats."
    explanation: Records the preparation and readout this model entry describes.
discussions:
- discussion_id: cfp-host-nav-susceptibility
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does variation in human voltage-gated sodium channel genes modify
    susceptibility to, or the symptom profile of, ciguatera fish poisoning?
  attaches_to:
  - pathophysiology#Voltage-Gated Sodium Channel Site 5 Activation
  rationale: >-
    Ciguatoxin acts directly on Nav1.1 to Nav1.9, and the isoform carrying a
    given symptom has been separated pharmacologically in rodents, so
    allelic variation at SCN1A, SCN9A, SCN10A or SCN11A is a biologically
    obvious candidate modifier of who becomes symptomatic and how. No human
    genetic association study exists. This entry deliberately has no `genetic:`
    section rather than one inferred from channel pharmacology, and that absence
    is the gap being recorded.
  evidence:
  - reference: PMID:28225079
    reference_title: "Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively."
    explanation: >-
      Establishes that different isoforms carry different symptoms, which is
      what makes host allelic variation a plausible modifier worth testing.
- discussion_id: cfp-chronic-phase-no-model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Every experimental model of ciguatera reproduces the acute channel lesion
    over minutes to hours. None reproduces the chronic relapsing syndrome that
    affects at least a fifth of patients for months to years. Does chronicity
    reflect persisting channel dysregulation, a sensitised nociceptive circuit,
    or something the acute models cannot express?
  attaches_to:
  - progression#Chronic ciguatera
  - pathophysiology#Repetitive Firing of Peripheral Sensory Afferents
  rationale: >-
    The mismatch matters because it is the chronic phase, not the acute one,
    that carries most of the disability, and every mechanistic claim about it in
    the literature is inference from acute pharmacology. The rat cold
    hypersensitivity model and the mouse CGRP release preparations recorded in
    this entry both measure an effect within hours of toxin application; neither
    has been run over the time course on which human symptoms relapse, and the
    reported triggers of relapse - alcohol, nuts, a further fish meal - have no
    counterpart in any model. Reactivation months after the toxin has cleared is
    not obviously a channel-occupancy phenomenon at all, which is what makes this
    a translational gap rather than a missing experiment.
  evidence:
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even though chronic CP cases are regularly reported, studies dedicated to the understanding of this phenomenon are scarce, especially due to the lack of a clear consensus regarding its clinical definition."
    explanation: States that the chronic phase is under-studied, which is the human side of the mismatch.
  - reference: PMID:34564650
    reference_title: "Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering that at least 20% of the persons affected by CP are likely to develop a persistent form"
    explanation: Establishes that the unmodelled phase is the common one, not an edge case.

📚

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 (2)

Record notes

Curated from a `claude_code` deep-research report (`research/Ciguatera_Fish_Poisoning-deep-research-claude_code.md`), whose reference validation resolved 38/38 identifiers and whose term validation resolved 41/41 CURIEs. Every ontology binding written here was nevertheless re-derived by a fresh lookup rather than copied from that report, per the repository's term contract; the report itself flags its suggested CURIEs as unverified. There is no GeneReviews chapter, and no OMIM entry, because this is an acquired toxicosis with no Mendelian basis - the `genetic:` section is deliberately absent rather than empty, and the open question of host voltage-gated sodium channel variation is recorded in `discussions` instead of being inferred from channel pharmacology. `clinical_trials:` is likewise empty because no NCT-registered ciguatera trial was found; the one randomised trial in the literature predates registration and is cited through the review that appraises it. Two mechanisms here are genuinely disputed and are curated as disputes rather than resolved. Where ciguatoxin acts on the heart is one: the clinical literature argues an indirect vagal-afferent and central-vasomotor route while mouse histology argues direct myocardial sodium channel activation, and the `Cardiac Conduction and Vasomotor Disturbance` node carries both with a `REFUTE` item against the indirect account. Whether intravenous mannitol works is the other, carried as a `SUPPORT`/`REFUTE` pair on the treatment and a second `REFUTE` on its mechanism link, where the nerve-preparation result and the intact-rat result disagree. Two causal edges are deliberately *not* drawn. Sodium channel activation does not cause the potassium current inhibition, so that node hangs off the ingestion node as a parallel branch of the same exposure; and repetitive firing does not cause the cold sensitisation, which is a sibling consequence of the same depolarisation. Both were initially drawn the wrong way round and corrected.

Create: Ciguatera Fish Poisoning · 2026-09-15T03:05:02Z · View source

New entry for ciguatera fish poisoning (MONDO:0043230), an environmental marine-biotoxin exposure disorder. Deep research: one run, provider claude_code, with no fallback (research/Ciguatera_Fish_Poisoning-deep-research-claude_code.md). Its own reference validation resolved 38/38 identifiers with a 0.0 confabulation rate; its term validation resolved 41/41 CURIEs with one mislabelling (HP:0001251 reported as 'Peripheral neuropathy/paresis, ataxia' where HPO calls it Ataxia) and two loose paraphrases (CL:0000540, UBERON:0002240). None of those three terms is bound in this entry. No CURIE was copied from the report: every binding was re-derived by a fresh runoak lookup at the moment it was written, per the CLAUDE.md term contract, and the report explicitly flags its own suggestions as unverified. Duplicate preflight: git grep over origin/main for MONDO:0043230 and 'ciguatera' across kb/ and stubs/ returned nothing; GitHub issue and PR searches across all states for 'ciguatera' returned zero results. GeneReviews baseline: not applicable and deliberately skipped. This is an acquired toxicosis with no Mendelian basis, so there is no GeneReviews chapter and no OMIM phenotype entry. The entry therefore carries no genetic: section at all; the open question of host voltage-gated sodium channel variation is recorded as a KNOWLEDGE_GAP discussion rather than inferred from channel pharmacology. References: 22 PMIDs fetched into references_cache/ via just fetch-reference. Most of the report's sources were cited by PMC id; those were converted to PMIDs through the NCBI ID converter rather than by guessing. Every reference_title was inserted programmatically by copying the title: frontmatter line out of the cached file, never written from having read the abstract. No DOI-keyed or preprint-keyed evidence items were used, so every snippet in this entry is covered by the gating validator. Content: a twelve-node causal chain running from Gambierdiscus toxin production on reef substrate, through trophic biotransformation and biomagnification, ingestion, voltage-gated sodium channel site 5 activation and concurrent potassium current inhibition, to sustained sodium influx and then four organ-level branches (peripheral sensory afferents with CGRP release and Nav1.8/TRPA1 cold sensitisation, nodal and adaxonal Schwann cell swelling, enteric and autonomic neurons, cardiac conduction). Seventeen phenotypes, three progression phases, four prevalence records, two environmental exposures, four treatments, two animal models and two discussions. Judgement calls worth flagging for review: - Cold allodynia is bound to HP:0012533 Allodynia with the cold qualifier carried in preferred_term. HPO has no cold-specific allodynia term; HP:0012534 Dysesthesia and HP:0010829 Impaired temperature sensation were both considered and neither names cold-evoked pain. - The food exposure is bound to ECTO:0000537 exposure to toxin, following the Acute_Ackee_Fruit_Intoxication precedent. ECTO was searched through sqlite:obo:ecto for a ciguatoxin, ciguatera or marine-biotoxin class and none exists; the descendants of ECTO:0000537 are mycotoxin, phytoalexin, phytotoxin, uremic toxin and virulence factor, and the fish-ingestion classes that exist name unrelated species. The reason is recorded in the entry's own notes. - The sea-surface-warming exposure is left with a free-text exposure_term and no term:, because ECTO's temperature classes describe an organism exposed to ambient heat and the warming here acts on the dinoflagellate habitat, not on the patient. - Mannitol carries a deliberate SUPPORT/REFUTE pair from the same review (PMID:28535116): the case-series evidence for it and the negative randomised trial against it, as separate items rather than one hedged item. - modifier: GAIN_OF_FUNCTION rather than INCREASED on the sodium channel node, because the claim is qualitative (the channel opens outside its voltage-dependent constraint), and there is no host variant anywhere in the entry for functional_impact_category to describe. - The Cook Islands veterinary series is recorded under a single species: Dog entry although it covers 165 dogs and 81 cats, because the slot is single-valued; the entry notes say so. - No datasets: block. No ciguatera-relevant repository accession was identified, and none was invented. Validation run on this tree: just validate (schema, terms, references) passes with 98/98 snippets verified; just validate-disorders (the authoritative batched check CI runs) passes; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence and check-enum-values all pass. Weighted compliance 90.1%. The remaining compliance gaps are uncited causal edges where no source makes the causal claim separately from the nodes it connects, and the absent datasets block.

Claude Code ▸

Ciguatera Fish Poisoning — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 46 citations 2026-09-15T02:38:11.232640

Ciguatera Fish Poisoning — Comprehensive Research Report

1. Disease Information

Overview. Ciguatera fish poisoning (CFP, "ciguatera") is an acquired, foodborne marine-toxin illness caused by eating fish (rarely certain invertebrates) whose flesh has bioaccumulated ciguatoxins (CTXs) — heat-stable, lipophilic, polycyclic polyether neurotoxins produced by benthic dinoflagellates of the genera Gambierdiscus and Fukuyoa. It is not an infection and not a genetic disorder; it is an environmentally acquired toxicosis whose severity and phenotype depend on toxin dose, congener mixture, and host factors. CFP produces a characteristic triad of gastrointestinal, neurological, and cardiovascular manifestations that begins acutely (minutes to ~72 h post-ingestion) and, in a substantial minority of patients, evolves into a chronic, relapsing neurological syndrome lasting weeks to years (Friedman et al., Marine Drugs 2017, PMC5367029; PMID:19005579).

Key identifiers. - MONDO: MONDO:0043230 (per curation target; MONDO models this as an acquired environmental disease, not a Mendelian disorder) - MeSH: D036841, "Ciguatera Poisoning" (Tree Number C25.723.415.246) — https://meshb.nlm.nih.gov/record/ui?ui=D036841 - ICD-10-CM: T61.0- family — T61.01XA (accidental/unintentional, initial encounter), T61.02XA (intentional self-harm), T61.03XA (assault), T61.04XA (undetermined); ICD-11 should be searched under the poisoning-by-marine-animal/toxin chapter (NE61 exposure category) - OMIM: none — CFP is not a Mendelian disease and has no OMIM phenotype entry, consistent with its purely acquired-toxicologic etiology - Orphanet: not indexed as a distinct rare-disease entity in the searches performed here; CFP is more commonly catalogued in toxicology/food-safety resources (NORD does carry a consumer-oriented entry: https://rarediseases.org/rare-diseases/ciguatera-fish-poisoning/) - Synonyms: ciguatera poisoning, ciguatera toxicosis, tropical fish poisoning, "ciguatera" (from Cuban Spanish cigua, referring to a marine snail once implicated); associated but distinct entities are scombroid poisoning, tetrodotoxin poisoning, and paralytic/neurotoxic/diarrhetic shellfish poisoning (PSP/NSP/DSP), which curators should not conflate with CFP despite overlapping "seafood poisoning" framing.

Evidence base. The bulk of the literature is aggregated disease-level clinical/epidemiological data (case series, outbreak investigations, retrospective cohort/registry analyses) rather than individual-patient EHR data — French Polynesia, Guadeloupe/Martinique, Hong Kong, Puerto Rico, Florida/CDC, and Pacific-island public-health datasets are the dominant sources (PMC4210881; PMC3339456; PMC5814543; PMC3236724; PMC9415704).

2. Etiology

Disease causal factor. CFP is caused exclusively by dietary ingestion of ciguatoxin-contaminated fish (occasionally other reef organisms) — it is a toxin-mediated, environmental disease with no infectious or Mendelian-genetic causal component. Ciguatoxins are secondary metabolites of epibenthic/epiphytic dinoflagellates in the genera Gambierdiscus (≥18 species, e.g., G. polynesiensis, G. excentricus, G. australes) and the sister genus Fukuyoa, which live on macroalgae and reef detritus in tropical/subtropical coral-reef ecosystems (PMC12854468; PMID:41610130). Herbivorous reef fish graze on toxin-laden algae; the biologically less-toxic precursor "gambiertoxins" are then oxidized by hepatic cytochrome P450 enzymes as they pass up the food chain into the far more potent ciguatoxins, which biomagnify in carnivorous apex reef predators (barracuda, grouper, snapper, moray eel, amberjack) (Mudge et al., Chemosphere 2023, PMID:37044143; Mudge et al., Toxicon 2024, PMID:38043714). Congeners differ by ocean basin: Pacific ciguatoxins (P-CTX-1, -2, -3), Caribbean ciguatoxins (C-CTX-1, -2), and Indian Ocean ciguatoxins (I-CTX) — a distinction relevant to potency and detection-assay cross-reactivity.

Genetic risk factors. No causal or susceptibility gene variants have been established for CFP; it is not modeled by ClinVar/GWAS as a genetic disease. There is no confirmed evidence of allelic variation in voltage-gated sodium channel genes (SCN1A–SCN11A) modulating human ciguatera susceptibility, although this is biologically plausible given the toxin's direct VGSC target and is an open research gap.

Environmental risk factors: - Consumption of large, carnivorous, apex-predator reef fish (barracuda, grouper, snapper, moray eel, amberjack) from endemic tropical/subtropical reef waters (Caribbean, Pacific, and increasingly Macaronesia/East and Southeast Asia) (PMC5367029; PMID:31927300). - Fish size/trophic position: larger, older predatory fish generally pose higher risk through biomagnification, though the size–toxicity relationship is site-specific and not a reliable universal predictor — fish weighing >2 kg accounted for >80% of Hong Kong CFP outbreak fish, but size was not predictive in French Polynesia (PMC9027493; ScienceDirect S0041010114000890). - Consumption of fish liver, roe, or viscera, which concentrate CTX more than muscle. - Sea-surface warming, coral-reef degradation, and habitat disturbance (storms, dredging, coastal construction) that promote Gambierdiscus/Fukuyoa proliferation on newly exposed algal substrate — climate-linked geographic range expansion of ciguatera risk zones is well documented (PMC12854468). - Sex and age are not strong independent risk factors for exposure per se (risk tracks with who eats the implicated fish), though physiological factors (see below) modulate presentation. - Repeated/sensitizing prior exposure: some evidence suggests prior ciguatera episodes lower the threshold for symptomatic recurrence on subsequent, even minor, toxin exposure ("sensitization") (PMC5367029).

Protective factors. No genetic protective alleles are established. The only well-supported "protective" factor is behavioral/environmental: avoidance of high-risk species/regions, avoidance of fish viscera, and (in some traditional Pacific practices) test-feeding to animals or ants before human consumption — none of which are validated, sensitive screening methods. There is no dietary or pharmacologic chemoprophylaxis with demonstrated efficacy.

Gene–environment interactions. None are established for CFP in the CTD/GxE literature; the dominant "interaction" reported is host-intrinsic pharmacodynamic variability (differential VGSC subtype expression/density in individual patients) rather than a documented allele-by-exposure interaction.

3. Phenotypes

CFP produces a multi-system, largely episodic/acute syndrome with a distinctive delayed-onset chronic neurological tail. Onset is typically 30 minutes–24 hours after ingestion (range 15 min–72 h) (PMC5367029; Louisiana DOH manual).

Gastrointestinal (earliest, usually first 24 h, self-limited over 1–2 days): - Nausea (HP:0002018), Vomiting (HP:0002013), Diarrhea (HP:0002014), Abdominal pain/cramps (HP:0002027) — very frequent (>70–90% of cases)

Neurological (may begin with or shortly after GI symptoms; can persist weeks–months–occasionally years): - Paresthesia (HP:0003401) — tingling of lips, tongue, extremities - Cold–hot temperature (thermal) allodynia/reversal — the pathognomonic feature: cold objects feel burning-hot and hot objects feel cold; there is no single dedicated HPO term, but this is best mapped under abnormal thermal sensation (consider HP:0031000-type "sensory neuropathy" branches, or free-text with Cold-induced dysesthesia) - Pruritus (HP:0000989), often severe and exacerbated by alcohol - Myalgia (HP:0003326), Arthralgia (HP:0002829) - Peripheral neuropathy/paresis, ataxia (HP:0001251) in severe cases - Headache (HP:0002315) - Blurred vision (HP:0000622), photophobia - Dysgeusia/metallic or unusual taste sensations - Dental pain or sensation of "loose teeth" - Dysuria (painful urination) - Sleep disturbance, nightmares, and rarely hallucinations - Anxiety (HP:0000739) and Depression (HP:0000716) are reported, particularly with chronic ciguatera

Cardiovascular (typically appear within the first day, can be life-threatening in severe cases): - Bradycardia (HP:0001662), Hypotension (HP:0002615), and cardiac arrhythmia — reviewed as an underappreciated but potentially serious complication (Cardiovascular Complications in Ciguatera Fish Poisoning, PMID:22574244)

Constitutional: fatigue (HP:0012378), diaphoresis/excessive sweating, chills

Dermatological (less common, described in case reports): chronic dermatitis with episodic erythema following ciguatoxin exposure (PMC10562083)

Phenotype characteristics: - Onset: acute, hours after a single contaminated meal; no congenital or pediatric-specific onset pattern (any age can be affected, generally correlating with reef-fish consumption). - Severity: dose-dependent, ranging from mild self-limited GI upset to severe, occasionally fatal, cardiovascular/respiratory compromise; case-fatality is low (<0.1% of reported cases) (PMC5367029). - Progression/course: classically triphasic — acute GI phase (day 1–2) → acute-subacute neurological/cardiovascular phase (days–weeks) → chronic ciguatera phase in ~20% of patients, with fluctuating fatigue, myalgia, and pruritus persisting months to years (ScienceDirect S1080603223000030; PMC8472944). - Frequency among affected individuals: GI symptoms in the large majority (>70–90%); neurological symptoms in most symptomatic patients; cold–hot reversal is frequently cited as characteristic but is not universal; cardiovascular signs are less common but clinically important. - Quality-of-life impact: chronic ciguatera syndrome (fatigue, pruritus, dysesthesias, and psychiatric symptoms lasting months–years) can be markedly disabling; no validated disease-specific QoL instrument was identified, though generic instruments (EQ-5D, SF-36) have been used in adjacent seafood-toxin research.

Suggested HPO terms: HP:0002018, HP:0002013, HP:0002014, HP:0002027, HP:0003401, HP:0000989, HP:0003326, HP:0002829, HP:0001251, HP:0002315, HP:0000622, HP:0001662, HP:0002615, HP:0012378, HP:0000739, HP:0000716.

4. Genetic/Molecular Information

CFP has no causal Mendelian gene — this section is largely not applicable in the conventional sense used for inherited disease curation: - Causal genes: none (environmental toxin exposure, not a germline or somatic mutation). - Pathogenic variants: not applicable; there is no ClinVar/HGMD entry for "ciguatera." - Somatic vs. germline: not applicable. - Modifier genes: none confirmed in humans, though differential expression/density of voltage-gated sodium channel (VGSC) subtypes (SCN1A/Na_V1.1, SCN9A/Na_V1.7, SCN10A/Na_V1.8, SCN11A/Na_V1.9) across peripheral sensory neurons plausibly modulates individual symptom phenotype (see mechanism, below) but this is inferred from channel pharmacology, not from human genetic-association studies. - Epigenetics: no disease-specific epigenetic studies identified. - Chromosomal abnormalities: not applicable.

What is molecularly characterized is the toxin itself, which is the appropriate target of curation: - Ciguatoxins are cyclic polyether compounds (13–14 fused ether rings), biosynthesized from precursor "gambiertoxins"/"gambierol"-type compounds by Gambierdiscus/Fukuyoa, and oxidatively activated in fish liver by cytochrome P450 enzymes (PMID:37044143; PMID:38043714). - Major human-relevant congeners: P-CTX-1 (most potent, Pacific), P-CTX-2, P-CTX-3, C-CTX-1/-2 (Caribbean), I-CTX (Indian Ocean); related toxins from the same dinoflagellates include maitotoxin and gambierone. - Molecular target: voltage-gated sodium channel (VGSC) site 5 on the α-subunit (CHEBI/GO terms below); ciguatoxins act as allosteric agonists, not channel blockers.

5. Environmental Information

Environmental factors (primary etiological axis for this disease): - Toxin-producing benthic dinoflagellates Gambierdiscus spp. and Fukuyoa spp. — taxonomically Dinophyta/Alveolata — colonizing dead coral, turf algae, and macroalgal surfaces in tropical/subtropical reef systems (PMC12854468; PMC8473099). - Reef disturbance (storms, bleaching, dredging, construction) that increases algal substrate available for dinoflagellate colonization. - Sea-surface temperature rise and broader climate change, associated with geographic range expansion of Gambierdiscus/Fukuyoa into temperate-adjacent waters (e.g., Macaronesia/Canary Islands, parts of East/Southeast Asia and even isolated temperate detections) (PMC12854468; PMC7761829; ScienceDirect topic review S1568988324001689). - Regional/seasonal variation in toxin production tied to nutrient availability and pH (PMC7761829).

Lifestyle factors: - Dietary reliance on reef fish (subsistence/artisanal fishing communities in the Pacific and Caribbean bear disproportionate risk). - Recreational/tourist consumption of reef fish (grouper, barracuda, snapper) in endemic regions, including via imported/exported fish in non-endemic countries (documented urban outbreaks, e.g., New York City, CDC MMWR 2010–2011). - Post-exposure dietary triggers of relapse: alcohol, caffeine, nuts/nut oils, chocolate, chicken, eggs, and reef fish/fish sauces are widely reported (though mechanistically unproven) to provoke recurrence of neurological symptoms for up to 6 months after the index poisoning; patients are counseled to avoid these for ~6 months (Poison Control; CDPH fact sheet; StatPearls NBK482511).

Infectious agents: none — CFP is not infectious and is not caused by bacteria, viruses, fungi, or parasites; it must be distinguished from bacterial seafood-associated illnesses (e.g., Vibrio spp.) and from scombroid (histamine) poisoning, which share an overlapping consumption context but a distinct toxin/mechanism.

6. Mechanism / Pathophysiology

Causal chain (ordered)

Dinoflagellate toxin production — Gambierdiscus/Fukuyoa spp. biosynthesize gambiertoxin/CTX precursors on reef algal substrate → these enter the marine food web via herbivorous grazing.
Trophic biotransformation and biomagnification — hepatic cytochrome P450 oxidation in herbivorous and omnivorous fish converts precursor toxins into more potent ciguatoxins, which accumulate preferentially in the liver, viscera, and (to a lesser but still hazardous degree) muscle of predatory reef fish → leads to highly concentrated CTX burden in apex-predator fish flesh consumed by humans.
Ingestion and absorption — human consumption of contaminated fish → CTX is absorbed across the gastrointestinal epithelium (lipophilic, heat-stable — cooking does not inactivate it) → leads to systemic distribution to excitable tissue (enteric neurons, peripheral sensory/autonomic neurons, cardiac conduction tissue, CNS).
Molecular target engagement — CTX binds with picomolar–nanomolar affinity as an allosteric agonist at neurotoxin receptor site 5 on the α-subunit of voltage-gated sodium channels (VGSCs), across multiple Na_V subtypes (Na_V1.1, Na_V1.6, Na_V1.7, Na_V1.8, Na_V1.9) with differential subtype selectivity (PMC5320492; PMC5618408) → causes a hyperpolarizing shift in the voltage-dependence of channel activation, slowed/incomplete inactivation, and increased channel open-probability at (or near) resting membrane potential.
Neuronal/cardiac hyperexcitability — this shift results in spontaneous, repetitive firing of peripheral sensory afferents, enteric neurons, autonomic fibers, and cardiac pacemaker/conduction cells, together with sodium- and secondary calcium-influx-driven depolarization and axonal swelling (PMC7602189; ScienceDirect chapter S2468748021000059).
Downstream cellular consequences — sustained Na⁺/Ca²⁺ influx activates intracellular calcium-dependent signaling cascades → leads to oxidative stress, mitochondrial dysfunction, and (in sustained/high-dose exposure) neuroinflammatory signaling and neuronal injury; CTX also inhibits delayed-rectifier and A-type K⁺ currents in dorsal root ganglion (DRG) neurons, further amplifying excitability (PMC4744673).
Neuropeptide release / neurogenic inflammation — calcium-influx-dependent release of CGRP (calcitonin gene-related peptide) from sensory afferents (via Na_V1.9/Na_V1.7/Na_V1.1 activation) triggers local neurogenic vasodilation and can propagate systemic autonomic effects, in part via a nitroxyl/TRPA1-linked pathway (PMC5618408).
Organ-level manifestations (branching):
Enteric nervous system branch: hyperexcitability of enteric/autonomic neurons → produces the early gastrointestinal phase (nausea, vomiting, diarrhea, cramping).
Peripheral sensory neuron branch: DRG/peripheral nerve hyperexcitability and altered cold-thermoreceptor (likely TRPM8/TRPA1-modulated) signaling → produces paresthesia, pruritus, myalgia, and the pathognomonic cold–hot temperature-reversal sensation, an effect experimentally reproduced as ionic cold-hypersensitivity of spinal neurons in ciguatera models (PMC4744673).
Cardiac conduction branch: VGSC-mediated hyperexcitability and altered autonomic tone acting on cardiac pacemaker/conduction tissue and vascular smooth muscle → produces bradycardia, hypotension, and arrhythmia (PMID:22574244).
CNS branch (higher-dose/prolonged exposure): CNS penetration and neuroinflammatory/neuroprotective transcriptional responses have been demonstrated in a murine brain gene-expression model after CTX-1 exposure, showing an acute anti-inflammatory, neuroprotective transcriptional signature superimposed on the excitotoxic insult (BMC Neuroscience 2010, "Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response") — this is a model-organism (mouse) finding and its direct translational fidelity to the human chronic syndrome is not established (flagged as a human–model mismatch candidate).
Chronic phase (inferred, mechanistically less well characterized) — persistent low-level channel dysregulation, sensitized nociceptive circuitry, and/or ongoing neuroinflammation are hypothesized to underlie the chronic ciguatera syndrome (fatigue, relapsing dysesthesia/pruritus, psychiatric symptoms lasting months–years), but the mechanistic basis of chronicity itself is inferred rather than directly demonstrated in humans (PMC8472944).

Category detail

Molecular pathways: VGSC site-5 allosteric agonism (GO:0005248 voltage-gated sodium channel activity; consider GO:0086006 for cardiac-specific VGSC activity in cardiac myocytes); downstream calcium-signal transduction (GO:0006816 calcium ion transport); CGRP-mediated neurogenic inflammation pathway.
Cellular processes: neuronal hyperexcitability/repetitive firing, calcium-dependent neuropeptide exocytosis, oxidative stress response (relevant GO: GO:0006979 response to oxidative stress), and (in model systems) an acute neuroinflammatory/neuroprotective transcriptional program (GO:0006954 inflammatory response).
Protein dysfunction: not a structural protein-misfolding disease; the relevant "dysfunction" is pharmacological/functional gain-of-activity at the wild-type VGSC protein (allosteric agonism), not a mutation-driven loss/gain of function — i.e., this is analogous to the dismech convention of modifier: GAIN_OF_FUNCTION applied to a non-genetic, toxin-driven activity state of ion-channel function, since there is no host variant to anchor a functional_impact_category.
Metabolic changes: hepatic cytochrome P450–mediated oxidative bioactivation occurs in the fish, not the human host; in the poisoned human, no distinct primary metabolic disease process has been characterized beyond the downstream oxidative-stress cascade above.
Immune system involvement: neuroinflammatory signaling is implicated as a downstream amplifier (see above); CFP is not an autoimmune or immunodeficiency-related disease.
Tissue damage mechanisms: oxidative stress and calcium-overload-mediated neuronal/axonal injury in peripheral sensory neurons; no established necrotic/fibrotic end-organ damage pattern in survivors, consistent with the largely functional/reversible nature of the toxicosis.
Biochemical abnormality: functional ion-channel dysregulation (VGSC gain-of-activity) rather than an enzyme deficiency or receptor structural defect.
Molecular profiling: disease-specific human transcriptomic/proteomic/metabolomic datasets were not identified in this search; the only omics-level data found is the murine brain transcriptomic study cited above (model-organism, not human).
Single-cell/spatial/multi-omics: none identified for CFP specifically.

Suggested GO terms: GO:0005248 (voltage-gated sodium channel activity), GO:0086006 (voltage-gated sodium channel activity involved in cardiac muscle cell action potential), GO:0006816 (calcium ion transport), GO:0006979 (response to oxidative stress), GO:0006954 (inflammatory response), GO:0019233 (sensory perception of pain). Suggested CL terms: CL:0000101 (sensory neuron), a dorsal root ganglion sensory neuron term, CL:0000540 (neuron, generic), CL:0000746 (cardiac muscle cell), CL:0000192 (smooth muscle cell) for vascular effects. (Exact CL CURIEs should be re-verified against the current Cell Ontology before binding — not confirmed via direct ontology lookup in this research pass.)

7. Anatomical Structures Affected

Organ level:
Primary: gastrointestinal tract (stomach, intestine), peripheral nervous system, cardiovascular system (heart, vasculature)
Secondary/complication-level: skin (pruritus, rare chronic dermatitis, PMC10562083), genitourinary system (dysuria), CNS (headache, sleep disturbance, rare hallucinations), musculoskeletal system (myalgia/arthralgia)
Body systems involved: digestive, peripheral/autonomic nervous, cardiovascular, integumentary, and (in chronic disease) psychiatric/behavioral
Tissue/cell level: enteric neurons and gut epithelium; peripheral sensory (dorsal root ganglion) neurons and unmyelinated/thinly myelinated afferent fibers; cardiac conduction-system and pacemaker cells; vascular smooth muscle
Subcellular level: plasma-membrane voltage-gated sodium channel complexes (site 5); relevant GO Cellular Component: GO:0005886 (plasma membrane), GO:0034706 (sodium channel complex); downstream mitochondrial oxidative-stress involvement (GO:0005739 mitochondrion)
Localization: diffuse/systemic rather than focal — bilateral, symmetric sensory disturbances are typical (no reported lateralization pattern)

Suggested UBERON terms: UBERON:0001555 (digestive tract), UBERON:0000010 (peripheral nervous system), UBERON:0002240 (spinal cord, for DRG-adjacent structures), UBERON:0000948 (heart), UBERON:0001981 (blood vessel), UBERON:0002097 (skin of body).

8. Temporal Development

Onset: acute, dose- and toxin-load-dependent, typically 30 min–24 h (range 15 min–72 h) after ingestion of contaminated fish; no congenital, pediatric-specific, or age-restricted onset — onset timing is exposure-anchored, not developmental (PMC5367029; Louisiana DOH).
Progression:
Stage 1 — Acute gastrointestinal phase: hours 0–24–48; nausea/vomiting/diarrhea/cramping, typically self-limited.
Stage 2 — Acute neurological/cardiovascular phase: overlapping with or shortly following Stage 1, lasting days to a few weeks; paresthesia, thermal reversal, pruritus, myalgia, bradycardia/hypotension.
Stage 3 — Chronic ciguatera phase: in an estimated ~20% of patients, fluctuating fatigue, myalgia, pruritus and neuropsychiatric symptoms persisting months to occasionally years (ScienceDirect S1080603223000030; PMC8472944).
Progression rate: variable — most cases resolve fully within 3–6 weeks; a substantial minority progress to the chronic phase.
Disease course pattern: predominantly self-limited/acute with a recognized relapsing-remitting chronic tail; recurrences can be re-triggered by re-exposure to trigger foods/beverages (alcohol, caffeine, nuts, fish) even long after the index poisoning.
Disease duration: self-limited in the majority; chronic/lifelong-feeling course (though generally not permanently disabling) in a minority; rare reports describe permanent nerve damage.
Remission: spontaneous in most cases; symptomatic treatment (mannitol acutely; amitriptyline/gabapentinoids for chronic neuropathic symptoms) may shorten or ameliorate — but not clearly cure — the course.
Critical periods/windows for intervention: early administration of IV mannitol (within the first 24–48 h) is reported anecdotally to produce the most dramatic neurological improvement, though rigorous trial evidence is lacking (see Diagnostics/Treatment sections).

9. Inheritance and Population

Inheritance pattern: none — CFP is an acquired environmental toxicosis, not a heritable disease. Penetrance, expressivity, anticipation, germline mosaicism, founder effects, consanguinity, and carrier frequency are not applicable.

Epidemiology: - CFP is considered the most prevalent phycotoxin-related seafood poisoning worldwide, with global burden estimates commonly cited at ~20,000–50,000 cases/year (PMID:31927300; PMC5367029; NORD). - Regional incidence: - French Polynesia: annual incidence ~18/10,000 population (2016) - Guadeloupe (French West Indies), 2013–2016: mean annual incidence 1.47/10,000 — roughly 5-fold higher than the 1996–2006 baseline for the same territory (PMC5814543) - Hong Kong: distinct, well-documented urban import-related outbreaks tied to specific high-risk reef fish species (PMC4210881) - Puerto Rico (Culebra): incidence surveys in 2005–2006 (PMC3339456) - Pacific Islands overall: substantial burden documented over 1998–2008 (PMC3236724) - True prevalence/incidence is widely regarded as significantly underestimated due to under-recognition of symptoms, absence of routine surveillance in many endemic regions, and reporting reluctance (tourism-economy concerns) (PMC5367029). - Case-fatality is low, <0.1% of reported cases.

Population demographics: - Affected populations are geographically rather than ethnically defined — coastal/island communities dependent on reef fishing (Pacific Islands, Caribbean) bear the highest burden; travelers/tourists to endemic regions and consumers of imported reef fish in non-endemic countries (documented US mainland and European outbreaks) are also affected. - Geographic distribution: historically endemic in the tropical/subtropical Pacific and Caribbean; documented range expansion since ~2000 into Macaronesia (Canary Islands, Madeira/Selvagens) and East/Southeast Asian waters, plausibly climate-change-linked (PMC12854468; PMC8402339; PMC3367630 [Canary Islands]). - Sex ratio: no strong, consistently reported sex-based susceptibility differential was identified; risk tracks with consumption patterns of implicated fish rather than intrinsic sex-linked biology. - Age distribution: all ages affected; severity in some reports is greater in young children and elderly patients, plausibly reflecting body-weight-normalized dose and comorbidity burden, though this was not rigorously quantified across the sources reviewed here.

10. Diagnostics

Clinical diagnosis is predominantly based on the characteristic symptom triad (GI → neurological → cardiovascular) with a temporally plausible exposure history to a high-risk reef fish species; no single confirmatory bedside clinical test exists.

Laboratory/biomarker and toxin-detection tests (mainly applied to the fish, not the patient, for outbreak confirmation/regulatory screening): - Mouse bioassay (MBA): historically the reference method for detecting CTX-group toxins in fish tissue but increasingly disfavored on animal-welfare grounds and for poor specificity/limited sensitivity; the EU CONTAM Panel has explicitly called for validated alternatives. - Receptor-binding assay (RBA): competition binding between CTX and radiolabeled or fluorescently labeled brevetoxin-2 for VGSC site 5; a fluorescence-based RBA (RBA_F) was developed as a non-radioisotope alternative (PMC4830512; PMC10818520); a chemiluminescent acridinium-brevetoxin ligand assay has also been evaluated (PMC6833909). - Cell-based assays (CBA): neuroblastoma (N2a) and other neuronal cell lines exploit CTX's VGSC-agonist cytotoxicity; a human SH-SY5Y neuronal cell assay has been used as an in-vitro toxicity model (ScienceDirect S1382668917301011). - ELISA/immunoassay: sandwich ELISA and the Hokama "stick test" enzyme immunoassay have been used for fish-tissue screening, with newer fluorescence-based sandwich ELISA formats reaching detection limits compatible with the FDA guidance level of 0.01 ppb (10 ppt) for CTX1B in fish (PMID:18623118; PMC4830512). - Analytical chemistry: LC-MS/MS is increasingly used as a specific, quantitative confirmatory method for CTX congeners in fish tissue in reference laboratories. - There is no validated, widely available clinical (human-serum/urine) biomarker assay for confirming ciguatera in a patient; diagnosis in clinical practice remains syndromic.

Imaging/functional/electrophysiology: not disease-specific; nerve conduction studies may show findings consistent with a sensory neuropathy in patients with prolonged neurological symptoms, but no CFP-specific electrophysiologic signature was identified in this search.

Genetic testing: not applicable — there is no genetic test for CFP.

Clinical criteria/differential diagnosis: CFP must be differentiated from scombroid (histamine) poisoning, paralytic/neurotoxic/diarrhetic/amnesic shellfish poisoning, tetrodotoxin poisoning, and Guillain-Barré syndrome or other acute peripheral neuropathies when the ingestion history is unclear.

Screening: no population-level screening program exists for asymptomatic individuals; the primary "screening" that occurs is regulatory/food-safety testing of harvested reef fish (see Prevention).

11. Outcome/Prognosis

Survival/mortality: generally excellent; case-fatality <0.1% of reported cases (PMC5367029). Death, when it occurs, is typically attributable to severe cardiovascular collapse or respiratory compromise in high-dose exposures.
Morbidity: acute morbidity from the GI/neurological/cardiovascular triad is usually self-limited (resolution in 3–6 weeks); chronic ciguatera syndrome (fatigue, myalgia, pruritus, dysesthesia, anxiety/depression) affects up to ~20% of symptomatic patients and can persist for months to years, with meaningful impact on daily functioning (ScienceDirect S1080603223000030; PMC8472944).
Predictors of chronicity: an exploratory hospital-based analysis from French Polynesia sought predictors of chronic ciguatera among hospitalized cases (PMC8472944); specific predictive factors identified there should be reviewed directly for detailed curation, but broadly, higher initial symptom severity and possibly repeated prior exposure are implicated as risk factors for chronic evolution.
Recovery potential: most patients recover fully; a minority experience prolonged/relapsing dysesthesia, and rare reports describe permanent peripheral nerve injury.
Complications: dehydration (from GI losses), cardiovascular instability requiring monitoring/support in severe cases, and psychosocial/occupational impact from chronic symptoms.
Prognostic factors: initial toxin dose, congener/toxin mixture, individual sensitization from prior episodes, and possibly timing of treatment (early mannitol administration is anecdotally associated with more rapid neurological improvement, though this is not established by rigorous trial evidence — see below).

12. Treatment

No specific antidote exists. Management is supportive and symptomatic.

Pharmacotherapy: - Intravenous mannitol (osmotic diuretic, NCIT treatment-term candidate: dietary/osmotic agent category) — the most extensively reported specific intervention: supported by four uncontrolled case series, one unblinded comparative trial, and multiple case reports describing rapid (within minutes to days) reduction in neurological symptoms when given early; however, the only randomized, double-blind controlled trial found no significant benefit over normal saline, and mannitol carries its own adverse-effect profile. Net evidence is therefore mixed/inconclusive, and mannitol is not established as clearly superior to supportive care (Clinical Toxicology 2017, tandfonline 10.1080/15563650.2017.1327664; PMC2579736). - Amitriptyline (tricyclic antidepressant) — reported in case series/reports to relieve pruritus, dysesthesia, and chronic neuropathic pain; considered most useful for the chronic neurological phase, generally requiring prolonged treatment to sustain benefit. - Other agents used with variable, case-report-level success for chronic neuropathic symptoms: gabapentin, pregabalin, fluoxetine, duloxetine, tocainide (a sodium-channel-blocking antiarrhythmic) (emedicine.medscape.com/article/813869-medication). - Symptomatic supportive medications: antiemetics and antidiarrheals for GI symptoms; antihistamines for pruritus; NSAIDs/analgesics for myalgia/arthralgia; atropine for symptomatic bradycardia; IV fluids for volume support/hypotension. - No approved pharmacogenomic guidance exists (not a PharmGKB/CPIC-covered condition).

Advanced therapeutics: gene therapy, cell therapy, RNA-based therapies, targeted therapies, and immunotherapies are not applicable to CFP; investigational small-molecule work includes rosmarinic acid and derivatives, patented for potential ciguatera treatment (US Patent 9060985), though clinical efficacy data were not identified in this search.

Surgical/interventional: none indicated; management is medical/supportive.

Supportive/rehabilitative care: hydration, symptom-targeted medication, and — for patients with prolonged neuropathic symptoms — potential benefit from standard chronic-pain rehabilitative approaches (physical therapy for myalgia/weakness), although disease-specific rehabilitation protocols were not identified.

Experimental/clinical trials: no active, disease-specific registered clinical trials with NCT identifiers were identified in this search; the one randomized controlled trial identified addressed mannitol vs. saline (cited above) but a specific NCT number was not surfaced by the search tools used.

Treatment outcomes: none of the pharmacologic agents studied (mannitol, TCAs, gabapentinoids, tocainide) has demonstrated clear superiority over another in controlled comparison; evidence quality across the board is low (predominantly case reports/series).

Treatment strategy: no formal clinical-practice-guideline algorithm was identified; management is empirical/symptom-driven, generally: supportive care first line → consider early mannitol for significant neurological symptoms (with informed acknowledgment of equivocal trial evidence) → TCA/gabapentinoid for persistent/chronic neuropathic symptoms → dietary trigger avoidance (fish, alcohol, caffeine, nuts) for up to 6 months post-episode to reduce relapse risk.

Suggested NCIT terms: NCIT:C15747 (Supportive Care), NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bindings for mannitol, amitriptyline, gabapentin, pregabalin, duloxetine, and tocainide (each should be verified against CHEBI/NCIT before binding).

13. Prevention

Primary prevention: avoidance of high-risk reef-fish species (barracuda, grouper, snapper, moray eel, amberjack, and in some regions parrotfish/triggerfish) sourced from known or suspected ciguatera-endemic waters; avoidance of fish liver, viscera, and roe. The FAO/WHO Codex Alimentarius Code of Practice for the Prevention or Reduction of Ciguatera Poisoning (CXC 83-2024) provides the current international framework for producer/processor-level risk reduction. In the US, the FDA has issued guidance for primary seafood processors to obtain harvest-location information for reef fish (grouper, amberjack, snapper, lionfish, king mackerel, barracuda) to assess ciguatoxin risk before distribution.
No reliable field test exists for consumers — ciguatoxin is odorless, tasteless, and heat-stable, so neither sensory inspection nor cooking prevents intoxication. Traditional folk tests (ant/animal test-feeding) are not validated and are not recommended as safety measures.
Secondary prevention/screening: regulatory-level fish testing using receptor-binding assays, ELISA, or LC-MS/MS in processing/export facilities in some jurisdictions; no population-based human screening program exists.
Tertiary prevention: post-episode dietary counseling to avoid known relapse-triggering foods/beverages (fish, alcohol, caffeine, nuts, chocolate, chicken, eggs) for approximately 6 months to reduce symptom recurrence.
Immunization: not applicable — no vaccine exists or is biologically relevant to a small-molecule toxin exposure of this kind.
Genetic counseling/screening: not applicable.
Public health interventions: harmful-algal-bloom (Gambierdiscus/Fukuyoa) monitoring programs in some endemic regions; public health education campaigns in endemic Pacific/Caribbean territories; import controls and species-specific fishing advisories/bans in some high-risk locales.
Environmental interventions: reef conservation to limit the coral/algal disturbance that promotes toxin-producing dinoflagellate proliferation is a plausible upstream intervention, though not a formal "prevention program" in the clinical sense.
Prophylaxis: no drug or procedure is established for chemoprophylaxis before consumption of at-risk fish.

14. Other Species / Natural Disease

Taxonomy of susceptible hosts: any vertebrate consuming ciguatoxic fish is potentially susceptible; documented naturally occurring CFP has been best characterized in companion animals — dogs (Canis lupus familiaris, NCBITaxon:9615) and cats (Felis catus, NCBITaxon:9685) — in the Cook Islands, where a three-part descriptive series (2011–2017 clinic records; 246 cases, 165 dogs and 81 cats) characterized demographic/temporal/spatial distribution, exposure history and case definition, and treatment/outcome (PMC7020132 / PMID:32158145; PMC7096299; PMC7429383 / PMID:32848300).
Natural disease and veterinary relevance: in dogs and cats, CFP presented as a multisystem toxicosis dominated by motor dysfunction (ataxia, paresis/paralysis, recumbency being common), with respiratory and gastrointestinal involvement especially prominent in dogs; reef/lagoon fish and moray eels were the most commonly implicated exposure sources. Treatment was primarily supportive (fluid therapy, muscle relaxants); survival exceeded 90%, with most fatalities occurring in the first week and average hospitalization of ~12.9 days.
Comparative pathology: the canine/feline presentation — dominated by motor/ataxic signs rather than the human-predominant sensory/GI triad — illustrates a species-dependent phenotype divergence attributable to differences in diet (scavenging fish carcasses/viscera, higher relative dose), body size/dose-normalization, and possibly differential VGSC subtype distribution across species; this is a notable point for any comparative-pathology or cross-species pathograph annotation.
Zoonotic potential/transmission: CFP is not transmissible between animals or from animal to human by contact — both human and animal cases arise independently from ingestion of toxin-contaminated fish, so this is a shared environmental exposure, not zoonotic transmission in the classical sense.
Orthologous genes: the molecular target (VGSC α-subunits) is highly conserved across vertebrates (fish, mammals), which is why fish themselves, along with mammals, are susceptible to CTX pharmacodynamics — this cross-species conservation underlies the utility of animal/cell models (see below).

15. Model Organisms

Mouse (in vivo): the traditional mouse bioassay (MBA) has been the historical reference method for detecting CTX-class toxins in fish extract, based on lethality/toxicity scoring, but is increasingly disfavored for animal-welfare and specificity/sensitivity reasons (EU CONTAM Panel). Separately, murine brain gene-expression profiling after CTX-1 exposure demonstrated an acute anti-inflammatory, neuroprotective transcriptional response superimposed on the excitotoxic insult (BMC Neuroscience, 2010) — a mechanistic (not diagnostic) mouse model.
Rodent dorsal root ganglion (DRG)/spinal neuron electrophysiology models: ex vivo/in vitro rodent sensory-neuron preparations have been used to demonstrate CTX-induced ionic mechanisms of cold hypersensitivity, directly modeling the human thermal-reversal phenotype (PMC4744673), and to show multiple Na_V-subtype involvement in CTX pathophysiology (PMC5320492) and CGRP release (PMC5618408).
Cell-based (in vitro) models:
Mouse neuroblastoma (N2a) cell-based assay (CBA) — the most widely used in vitro surrogate for CTX potency/toxicity screening.
Human SH-SY5Y neuronal cell line — used to demonstrate potent cytotoxic effects of P-CTX-3C, providing a human-cell in vitro toxicity model (ScienceDirect S1382668917301011).
Heterologous expression systems (e.g., Xenopus oocytes or mammalian cell lines expressing individual cloned Na_V subtypes) underlie the subtype-selectivity electrophysiology studies cited above (PMC5320492).
Zebrafish: no CFP/ciguatoxin-specific zebrafish study was identified in this search, though zebrafish are an established general platform for neurotoxin/venom screening and represent a plausible, currently underexploited model for ciguatoxin research given their genetic tractability and high-throughput behavioral assays.
Model limitations: the mouse bioassay's poor specificity/sensitivity and animal-welfare concerns are explicitly noted as drivers for developing alternative (receptor-binding, cell-based, immunoassay) methods. No model fully recapitulates the human chronic ciguatera syndrome — chronicity itself has not been modeled in any organism identified in this search, representing a clear translational/human-model-mismatch gap worth flagging in any dismech discussions block (kind: HUMAN_MODEL_MISMATCH) if this disease is curated.
Applications: current models are used almost exclusively for (a) toxin detection/potency quantification in fish (regulatory/food-safety use) and (b) acute electrophysiological/mechanistic dissection of VGSC-subtype pharmacology and peripheral sensory hyperexcitability — not for therapeutic drug screening or for modeling the chronic human syndrome.

Summary of Key Evidence Gaps for Curation

No confirmed human genetic-susceptibility literature exists — any curated genetic block should record this as an absence rather than infer VGSC-gene involvement from toxin pharmacology alone.
Chronic ciguatera syndrome pathophysiology is mechanistically under-characterized in humans and has no established animal model — a strong HUMAN_MODEL_MISMATCH candidate.
Mannitol's efficacy remains genuinely contested (RCT-negative vs. case-series-positive) — evidence should be curated with explicit SUPPORT/REFUTE items from both the RCT and the case-series literature rather than presenting mannitol as established therapy.
Exact CHEBI/GO/CL/UBERON CURIEs proposed above are suggestions based on general biology and were not individually confirmed via a live ontology lookup in this research pass — per standard curation practice, each should be re-verified (e.g., via OAK/runoak) before being written into a KB entry, rather than bound from this report directly.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	38
Resolved	38
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	38
On topic	28
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	41
Resolved	41
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	29
Terms named correctly	26
Terms named as a different term	1
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001251 (2 mentions) - the report calls it "Peripheral neuropathy/paresis, ataxia"; HP calls it Ataxia

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000540 (1 mention) - the report calls it "neuron, generic"; CL calls it neuron
UBERON:0002240 (1 mention) - the report calls it "spinal cord, for DRG-adjacent structures"; UBERON calls it spinal cord, and lists "spinal cord structure" among its other names

Ask OpenScientist

OpenScientist Report

Mappings

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

Deep Research

Ciguatera Fish Poisoning — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (ordered)

Category detail

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

Summary of Key Evidence Gaps for Curation

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look