Cranial Neuralgia

Complex MONDO:0016374 Pathograph 16 Show in embeddings browser neuralgia cranial nerve neuropathy

Cranial neuralgia is paroxysmal, severe, lancinating pain confined to the sensory territory of a cranial (or, by clinical convention, an upper cervical) nerve, characteristically provoked by innocuous stimulation of a trigger zone. In the nerve-defined forms that dominate the category — trigeminal neuralgia by a wide margin, then glossopharyngeal and nervus intermedius neuralgia — the best-supported mechanism is chronic pulsatile compression of the nerve root by an overlying artery close to its entry into the brainstem. That compression produces focal demyelination and juxtaposition of bare axons, which favours ectopic impulse generation and ephaptic cross-talk between large tactile afferents and nociceptive fibres; synchronized high-frequency afterdischarge is then experienced as an abrupt shock-like paroxysm. The same demyelinating lesion is reached by other routes in secondary disease, most often a pontine multiple sclerosis plaque or a posterior fossa tumour compressing the root. Sodium-channel-blocking anticonvulsants (carbamazepine, oxcarbazepine) suppress the high-frequency firing and are first-line; microvascular decompression removes the compressive lesion itself and gives the most durable medication-free relief.

Ask OpenScientist

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

Submitting...

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

📘

Definitions

Paroxysmal cranial neuralgia pain phenotype

Recurrent brief shock-like pain restricted to the distribution of a single cranial nerve, of abrupt onset and termination, usually unilateral.

OTHER Applies across the nerve-defined subtypes; does not by itself distinguish classical from secondary aetiology.

Show evidence (1 reference)

PMID:38575268 SUPPORT Human Clinical

"Trigeminal neuralgia and glossopharyngeal neuralgia are craniofacial pain syndromes characterized by recurrent brief shock-like pains in the distributions of their respective cranial nerves."

States the shared paroxysmal, nerve-territory-confined pain phenotype that defines the category.

Aetiological classification of trigeminal neuralgia

Three-category aetiological grading: classical (imaging shows vascular compression with morphological change of the nerve root), secondary (an identifiable underlying neurological disease), and idiopathic (no cause found).

DIAGNOSTIC_CRITERIA Developed for trigeminal neuralgia and extended by analogy to the other cranial neuralgias, where it has not been separately validated.

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic."

Gives the three aetiological categories verbatim as proposed by the classification working group.

PMID:39847207 SUPPORT DIRECT Human Clinical

"Like trigeminal neuralgia, NIN can be divided into classic, idiopathic, secondary, or painful neuropathy."

Supports extension of the same scheme to nervus intermedius neuralgia, though this review notes the evidence base for that subtype is thin.

◆

Subtypes

Trigeminal Neuralgia (CN V) MONDO:0008599

By far the commonest cranial neuralgia. Pain is confined to one or more divisions of the trigeminal nerve, most often the maxillary and mandibular divisions, and is almost always unilateral. Severe neurovascular contact at the trigeminal root entry zone, usually arterial, is the dominant classical aetiology.

Show evidence (1 reference)

PMID:25231219 SUPPORT Human Clinical

"It affected solely the second and/or third trigeminal branch in 109 (69%) while the first branch alone was affected in only 7 (4%)."

Prospective series quantifies the divisional distribution that characterises this subtype.

Glossopharyngeal Neuralgia (CN IX) MONDO:0016372

Paroxysmal pain in the posterior tongue, tonsillar fossa, pharynx, and deep ear, triggered by swallowing, talking, or coughing. Compression of the glossopharyngeal and vagal rootlets near the medulla is the usual classical cause. Because the glossopharyngeal nerve carries the carotid-sinus afferent limb, attacks can recruit vagal reflex arcs and produce bradycardia, hypotension, and cardiac syncope -- rare, but the one way a cranial neuralgia becomes immediately dangerous.

Show evidence (1 reference)

PMID:28263933 SUPPORT Human Clinical

"Classic GPN is usually caused by pulsatile neurovascular compression of the glossopharyngeal and vagus rootlets."

Operative series identifies rootlet compression as the usual classical aetiology of this subtype.

Nervus Intermedius (Geniculate) Neuralgia (CN VII sensory root)

A rare neuralgia of the sensory branch of the facial nerve, producing deep ear pain that may radiate to the auditory canal, auricle, mastoid, soft palate, temple, and angle of the jaw. Compression by the anterior inferior cerebellar artery is the most commonly described cause. Diagnosis is confounded by overlap with trigeminal and glossopharyngeal territory.

Show evidence (4 references)

PMID:39847207 SUPPORT Human Clinical

"NIN presents as a rare neuralgia of this nerve, causing deep ear pain, which may radiate to the auditory canal, auricle, mastoid, soft palate, temple, and angle of the jaw."

Defines the pain territory of this subtype.

PMID:39847207 SUPPORT Human Clinical

"neurovascular compression involving the anterior inferior cerebellar artery is the most common etiology described"

Identifies the offending vessel for the classical form of this subtype.

PMID:30095334 SUPPORT Human Clinical

"Geniculate neuralgia (GN) is an uncommon craniofacial pain syndrome attributable to nervus intermedius (NI) dysfunction."

Surgical series defining the subtype by the nerve involved, which is the axis this entry's subtypes are cut along.

+ 1 more reference

Occipital Neuralgia (greater, lesser, and third occipital nerves)

Paroxysmal lancinating pain in the distribution of the greater, lesser, or third occipital nerves over the posterior scalp. Included here by ICHD-3 clinical convention and by the HPO neuralgia hierarchy, but mechanistically the outlier of this entry: these are branches of the C2-C3 dorsal rami rather than cranial nerves, and the described compression points lie extracranially along the nerve's course, not at a brainstem root entry zone. See the entry-level notes.

Show evidence (1 reference)

PMID:24737457 SUPPORT Human Clinical

"Occipital neuralgia is an uncommon cause of occipital pain characterized by paroxysmal lancinating pain in the distribution of the greater, lesser or third occipital nerves."

Establishes the pain character and nerve territory that place this alongside the cranial neuralgias.

Discussions and Knowledge Gaps

Is the demyelination-and-ephaptic-cross-excitation mechanism, established for the trigeminal root, actually the mechanism in glossopharyngeal and nervus intermedius neuralgia, or is it assumed by analogy?

KNOWLEDGE GAP OPEN gap_cn_ephaptic_mechanism_beyond_trigeminal

Attached to

pathophysiology#Ectopic Discharge and Ephaptic Cross-Excitation

The histopathology that grounds this entry's central mechanism comes from trigeminal nerve roots obtained at decompression surgery. Glossopharyngeal and nervus intermedius neuralgia are supported by operative observation of rootlet compression and by the fact that decompression relieves them, which is consistent with the same mechanism but does not demonstrate it — no comparable histological series of demyelination and axonal juxtaposition in those roots is available, and the operations are far rarer. Love and Coakham argue the generalisation explicitly, but on clinical and electrophysiological grounds rather than pathological ones. This matters for the concept decision recorded in this entry's notes: the case for one disease rather than a grouping rests on the generalisation holding.

Show evidence (2 references)

PMID:11701590 SUPPORT DIRECT Human Clinical

"Clinical observations and electrophysiological studies support the concept that demyelination and ephaptic spread of excitation underlie most, if not all, of these conditions."

The generalisation this gap questions, in the authors' own words. Note what it rests on -- clinical observation and electrophysiology, not the histology that grounds the trigeminal case.

PMID:28263933 SUPPORT INDIRECT Human Clinical

"Classic GPN is usually caused by pulsatile neurovascular compression of the glossopharyngeal and vagus rootlets."

Operative observation of compression in the glossopharyngeal subtype, which is consistent with the shared mechanism but establishes the compression rather than the demyelination or the ephaptic step.

Why do most people with severe neurovascular contact never develop a neuralgia, and what determines which compressed nerves become symptomatic?

KNOWLEDGE GAP OPEN gap_cn_compression_insufficient

Attached to

pathophysiology#Neurovascular Compression at the Nerve Root Entry Zone

Neurovascular contact is present on 36% of asymptomatic nerves, and even severe contact appears on 13% of asymptomatic sides. Compression is therefore necessary-ish but plainly not sufficient, and the sex difference in how often severe contact explains the pain — 75% of men versus 38% of women — implies that a substantial fraction of disease, particularly in women, is driven by something this graph does not represent. Candidates have been proposed rather than the field being empty: a 2022 systematic review of the neurovascular compression syndromes lists demyelination, root-entry-zone remodelling, vasculature pathology, nucleus hyperexcitability, white- and grey-matter change, and ion-channel disturbance as changes that must coexist with the compression, and this entry's own STIM1/SOCE discussion and its C8B and MFGE8 susceptibility records point at an inflammatory background from a different direction. What is missing is not candidates but demonstration: none is established as the necessary second hit, and none has been shown to account for the sex difference specifically.

Show evidence (3 references)

PMID:27306631 SUPPORT Human Clinical

"neurovascular contact was found in 471 out of 531 symptomatic nerves (89%) and 244 of 681 asymptomatic nerves (36%), indicating high sensitivity but poor specificity."

Meta-analytic figures establishing that contact is common on asymptomatic nerves, which is the gap.

PMID:25616608 SUPPORT Human Clinical

"Severe NVC was much more prevalent in men than in women, who may more often have other disease etiologies causing or contributing to TN."

The authors themselves infer from the sex difference that a substantial share of disease in women has a different aetiology, which is the unrepresented factor this gap names.

PMID:35860499 SUPPORT Human Clinical

"The systematic review suggests that the anatomical and/or hemodynamical changes described are insufficient to account for NVC-related symptoms by themselves. They must coexist with additional changes such as factors associated with the affected nerve (e.g., demyelination, REZ modeling,..."

Systematic review of 63 papers stating both halves of this gap: that compression alone is insufficient, and which co-factors have been proposed. It is the source for rewording this rationale, which previously claimed no candidate had been proposed at all.

Does STIM1/ORAI1 store-operated calcium entry and T-cell cytokine release contribute causally to human cranial neuralgia, or is the neuroinflammatory signal a consequence of nerve injury rather than a driver of it?

KNOWLEDGE GAP OPEN gap_cn_stim1_soce_neuroinflammation

Attached to

pathophysiology#Focal Demyelination and Axonal Juxtaposition

A 2024 study reports STIM1 overexpression in trigeminal neuralgia patients by microarray reanalysis, and links STIM1-dependent store-operated calcium entry to TNF-alpha, IL-1beta, and IL-6 release from T lymphocytes in rat models. It is deliberately not modelled as a pathophysiology node here: the human component is bioinformatic reanalysis of deposited expression data rather than a measurement in patient tissue, the causal work is in the same rat constriction model this entry already flags as a poor human proxy, and nothing establishes direction -- immune activation around an injured nerve is expected downstream of demyelination, so finding it does not show it drives the disease. The complement and neuroinflammation genes in this entry's `genetic:` section point at the same unresolved question from a different direction, which is the reason to record it rather than drop it.

Show evidence (2 references)

DOI:10.3389/fnmol.2024.1391189 SUPPORT INDIRECT Computational

"Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression."

The human-facing claim, which rests on reanalysis of deposited expression data rather than a measurement made in patients. Marked INDIRECT and graded COMPUTATIONAL for that reason, against the paper's own stronger wording.

DOI:10.3389/fnmol.2024.1391189 SUPPORT INDIRECT Model Organism

"Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development."

The mechanistic claim, made in rat models and in vitro. Marked INDIRECT because it does not establish that the pathway operates, or operates causally, in human disease.

Do rodent nerve-constriction models reproduce the mechanism of human cranial neuralgia well enough for their sodium-channel findings to be transferred to it?

HUMAN MODEL MISMATCH OPEN gap_cn_rodent_constriction_model_fidelity

Attached to

pathophysiology#Dysregulated Voltage-Gated Sodium Channel Expression

The subunit-level detail in this entry's channel node comes from infraorbital-nerve chronic constriction injury in rats. That model injures a distal peripheral branch, whereas the human lesion is focal demyelination of the central, oligodendrocyte-myelinated segment of the root, and it produces sustained mechanical hypersensitivity rather than the triggered, paroxysmal, remitting pattern that defines the human disease. Devor and colleagues state plainly that there are no satisfactory animal models of trigeminal neuralgia and that the mechanistic account is a deduction awaiting patient data. The direction of change for individual channels should therefore be read as model-derived and not as a human finding.

Show evidence (2 references)

PMID:11803297 SUPPORT Other

"There are no satisfactory animal models of trigeminal neuralgia, and it is difficult to obtain essential data from patients."

States the model gap directly, and is why the mechanistic account in this entry is a deduction rather than a demonstration.

PMID:27327156 SUPPORT DIRECT Model Organism

"Behavioral tests showed that the mechanical pain threshold decreased significantly 4-42 days after surgery and reached the lowest observed value by day 12."

The model's readout is a sustained drop in mechanical threshold over weeks, not the triggered, brief, remitting paroxysms that define the human disease -- the specific behavioural mismatch this gap is about.

⚙

Pathophysiology

Neurovascular Compression at the Nerve Root Entry Zone

An arterial loop, less often a vein, contacts the sensory nerve root close to its entry into the brainstem and indents, displaces, or flattens it. Contact alone is common on asymptomatic nerves and is not sufficient; it is the morphological change — displacement or atrophy — that is specific to the symptomatic side, and its location at the root entry zone that carries the diagnostic weight. The compression is pulsatile, so the mechanical insult is delivered with every arterial cycle over years.

trigeminal nerve root UBERON:0004673 superior cerebellar artery UBERON:0001635

Downstream

Focal Demyelination and Axonal Juxtaposition Chronic compression at the root strips myelin over a short segment and brings bare axons into direct apposition without intervening glial processes.

Show evidence (3 references)

PMID:25541189 SUPPORT Human Clinical

"severe neurovascular contact was highly prevalent on the symptomatic compared to the asymptomatic side [53% versus 13%, P < 0.001, odds ratio = 11.6 (4.7-28.9), P < 0.001]. Severe neurovascular contact was caused by arteries in 98%."

Blinded 3T MRI study establishing that it is severe contact, arterial in almost all cases, that associates with the painful side.

PMID:25541189 SUPPORT Human Clinical

"severe neurovascular contact is involved in the aetiology of classical trigeminal neuralgia and that it is caused by arteries located in the root entry zone"

Localises the aetiologically relevant compression to the root entry zone specifically.

PMID:27306631 SUPPORT INDIRECT Human Clinical

"neurovascular contact was found in 471 out of 531 symptomatic nerves (89%) and 244 of 681 asymptomatic nerves (36%), indicating high sensitivity but poor specificity."

Meta-analytic figures showing why mere contact is insufficient, which is why this node is framed as morphological compression rather than contact.

Focal Demyelination and Axonal Juxtaposition

The compressed segment of the root loses myelin and demyelinated axons come to lie against one another with no glial process between them. Because the proximal root is a central-nervous-system segment, the myelinating cell involved there is the oligodendrocyte rather than the Schwann cell. This is the lesion that the two aetiological routes of this disease converge on: vascular compression reaches it mechanically, multiple sclerosis reaches it immunologically, and a posterior fossa tumour reaches it by mass effect.

oligodendrocyte CL:0000128

myelin maintenance GO:0043217 ↓ DECREASED

trigeminal nerve root UBERON:0004673

Downstream

Ectopic Discharge and Ephaptic Cross-Excitation Bare, closely apposed axons permit spontaneous impulse generation and direct electrical spread from one fibre to its neighbours.

Dysregulated Voltage-Gated Sodium Channel Expression Demyelinating injury of the root is followed by a change in which sodium-channel subunits the affected sensory neurons express and where those channels sit in the membrane.

Show evidence (2 references)

PMID:11701590 SUPPORT Human Clinical

"There is now persuasive evidence that trigeminal neuralgia is usually caused by demyelination of trigeminal sensory fibres within either the nerve root or, less commonly, the brainstem."

States demyelination of the sensory fibres as the usual proximate cause, the claim this node represents.

PMID:11701590 SUPPORT Human Clinical

"In most cases, the trigeminal nerve root demyelination involves the proximal, CNS part of the root and results from compression by an overlying artery or vein."

Establishes that the demyelinated segment is the central (oligodendrocyte-myelinated) part of the root.

Dysregulated Voltage-Gated Sodium Channel Expression

Injured trigeminal sensory neurons remodel their voltage-gated sodium channel complement, lowering the threshold for impulse initiation and supporting repetitive high-frequency firing. This is the node that the first-line drugs act on: carbamazepine and oxcarbazepine stabilize the inactivated state of these channels. The specific subunit pattern is characterised mainly in rodent nerve-injury models rather than in human tissue, so the identity of the individual channels is held less firmly than the fact of the dysregulation.

trigeminal ganglion sensory neuron CL:4023169

regulation of membrane potential GO:0042391 ⚠ ABNORMAL

voltage-gated sodium channel activity GO:0005248 ↕ DYSREGULATED

trigeminal ganglion UBERON:0001675

Animal models

Rat infraorbital nerve chronic constriction injury Rat partially recapitulates The model does reproduce injury-driven remodelling of voltage-gated sodium channel expression in trigeminal ganglion neurons, which is the claim this node makes.

Downstream

Ectopic Discharge and Ephaptic Cross-Excitation A lowered firing threshold and altered channel kinetics make the injured afferents hyperexcitable, which is the precondition for the synchronized afterdischarge that generates a paroxysm.

Show evidence (2 references)

PMID:31908187 SUPPORT Human Clinical

"Classic trigeminal neuralgia is associated with neurovascular compression in the trigeminal root entry zone, which can lead to demyelination and a dysregulation of voltage-gated sodium channel expression in the membrane. These alterations may be responsible for pain attacks in trigeminal..."

Quoted as a contiguous pair so the referent of the pronoun sits inside the quote rather than outside it -- the alterations named are the channel dysregulation this node represents.

PMID:27327156 SUPPORT INDIRECT Model Organism

"trigeminal ganglion in rats subjected to an infraorbital nerve-chronic constriction injury showed upregulation of Nav1.3 and downregulation of Nav1.7, Nav1.8, and Nav1.9 messenger RNA and protein levels"

Rodent constriction-injury data give the direction of change for individual subunits. Marked INDIRECT because the model injures a peripheral trigeminal branch rather than reproducing root-entry-zone demyelination, and the subunit pattern has not been confirmed in human trigeminal ganglion.

Ectopic Discharge and Ephaptic Cross-Excitation

At the demyelinated segment, impulses arise where they should not and spread laterally between apposed bare axons. A light touch carried by large tactile afferents can therefore ignite activity in nociceptive fibres, and the resulting cross-excitation is amplified into a synchronized high-frequency burst. This is the step that explains the two features nothing else in the disease accounts for: that an innocuous stimulus in a small trigger zone provokes severe pain, and that the paroxysm builds, peaks, and stops abruptly with a refractory period afterwards.

trigeminal ganglion sensory neuron CL:4023169

neuronal action potential GO:0019228 ↑ INCREASED action potential propagation GO:0098870 ⚠ ABNORMAL

Downstream

Paroxysmal Neuralgiform Pain The synchronized burst reaching central trigeminal pathways is experienced as a brief, abrupt, electric-shock-like paroxysm in the nerve's territory.

Show evidence (4 references)

PMID:11701590 SUPPORT Human Clinical

"Clinical observations and electrophysiological studies support the concept that demyelination and ephaptic spread of excitation underlie most, if not all, of these conditions."

Explicitly generalises the demyelination-plus-ephaptic-spread mechanism across the vascular-compression cranial nerve hyperactivity syndromes, which is the basis for curating these subtypes on one pathograph.

PMID:35860499 SUPPORT Human Clinical

"Clinically, we can distinguish the following NVC conditions: trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. Also, rare cases of geniculate neuralgia and superior laryngeal neuralgia are reported."

Independent corroboration of the lump/split decision from a 2022 systematic review of 63 papers, two decades after Love and Coakham. It places trigeminal, glossopharyngeal, and geniculate (nervus intermedius) neuralgia on the same neurovascular-compression mechanism, which is the generalisation this entry's one-disease structure depends on.

PMID:11803297 SUPPORT Other

"The ignition hypothesis accounts for the major positive and negative signs and symptoms of trigeminal neuralgia, for its pathogenesis, and for the efficacy of treatment modalities."

The ignition formulation is the mechanistic account this node encodes.

+ 1 more reference

Paroxysmal Neuralgiform Pain

The clinical endpoint of the graph: abrupt, severe, stabbing or electric-shock-like pain lasting seconds to two minutes, confined to the territory of the affected nerve, recurring in volleys and typically evoked by an innocuous trigger. Complete remissions lasting weeks to years are characteristic and distinguish it from most other neuropathic pain.

sensory perception of pain GO:0019233 ↑ INCREASED

Animal models

Rat infraorbital nerve chronic constriction injury Rat fails to recapitulate The model does not reproduce the defining clinical phenotype. Human cranial neuralgia is brief, trigger-evoked, and remitting; the model produces a sustained lowering of mechanical threshold over weeks.

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Typical characterizations include notions of brief, sudden, stabbing, electric shock–like, and severe pain attacks."

Describes the pain quality this outcome node represents.

PMID:27306631 SUPPORT Human Clinical

"Unlike other forms of neuropathic pain, TN enters into periods of complete remission in up to 63% of patients."

Supports the remitting-relapsing course stated in this node's description.

Trigger Zone Mechanical Provocation

Innocuous mechanical stimulation of a confined cutaneous or intraoral trigger zone — chewing, talking, shaving, a breath of cold air, or, for glossopharyngeal neuralgia, swallowing — sets off a paroxysm. Evoked attacks are so nearly universal in classical trigeminal neuralgia that their presence is a diagnostic criterion. Triggerability has been interpreted as a sign of cross-excitation between tactile and nociceptive fibres, which is the reading this graph follows, but it is an interpretation rather than a directly demonstrated coupling.

detection of mechanical stimulus involved in sensory perception GO:0050974

Downstream

Ectopic Discharge and Ephaptic Cross-Excitation Afferent traffic from the trigger zone enters the demyelinated segment and ignites cross-excitation into nociceptive fibres.

Show evidence (1 reference)

PMID:27306631 SUPPORT Human Clinical

"In the few studies that examined trigger stimuli or maneuvers in classical TN, evoked pain was reported in 99% of the patients."

Quantifies how nearly universal trigger-evoked pain is, supporting this as a mechanism node rather than an incidental feature.

Central Demyelinating Plaque in Multiple Sclerosis

In secondary disease due to multiple sclerosis, an inflammatory demyelinating plaque involving the pontine trigeminal pathways or the root entry zone produces the same demyelinated, bare-axon segment that vascular compression produces mechanically. Increased susceptibility of the root to coexisting neurovascular contact has also been proposed. Bilateral disease, which is otherwise almost unknown, should raise suspicion of this route.

oligodendrocyte CL:0000128

Downstream

Focal Demyelination and Axonal Juxtaposition The plaque is itself the demyelinating lesion, so this route enters the shared graph at the demyelination node rather than upstream of it.

Show evidence (2 references)

PMID:11701590 SUPPORT Human Clinical

"Similar foci of nerve root demyelination and juxtaposition of axons have been demonstrated in multiple sclerosis patients with trigeminal neuralgia."

Human pathology showing that the MS route converges on the same histological lesion.

PMID:27306631 SUPPORT DIRECT Human Clinical

"The development of pain paroxysms has variably been explained with the presence of demyelinating plaques in the pons or increased susceptibility of the trigeminal nerve root to neurovascular compression."

Records that both explanations for MS-associated disease remain on the table, which is why this node is not asserted as a single settled route.

Posterior Fossa Mass Compressing the Nerve Root

A cerebellopontine-angle tumour, most often benign, compresses the root near its entry into the pons and induces focal demyelination in the same way an artery does. Malignant tumours behave differently: they tend to infiltrate the nerve and cause axonal degeneration, which produces a sensory deficit and a pain phenotype that does not resemble neuralgia. Tumour and multiple sclerosis together account for roughly 15% of trigeminal neuralgia, which is why imaging is required rather than optional.

trigeminal nerve root UBERON:0004673

Downstream

Focal Demyelination and Axonal Juxtaposition Mass effect at the root entry zone produces the same focal demyelinating lesion as arterial compression.

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Tumors leading to TN are mostly benign and typically compress the root near its entry into the pons. The compression induces focal demyelination and is thought to trigger paroxysmal ectopic discharges."

States the tumour-compression-to-demyelination-to-ectopic-discharge route this node represents.

PMID:27306631 SUPPORT Human Clinical

"A tumor at the cerebellopontine angle or MS causes TN in 15% of patients."

Quantifies the combined secondary-aetiology fraction cited in this node's description.

Extracranial Entrapment of the Occipital Nerves

The mechanism proposed for occipital neuralgia, and the reason that subtype sits apart from the rest of this entry. The greater, lesser, and third occipital nerves are compressed at defined points along their extracranial course — where the greater occipital nerve curves around the obliquus capitis inferior, pierces the semispinalis capitis and trapezius, and crosses the occipital artery. There is no brainstem root entry zone involved, and this node is deliberately not connected to the demyelination-and-ephaptic chain, because the evidence for that chain comes from cranial nerve roots and has not been shown for these nerves.

Downstream

Paroxysmal Neuralgiform Pain Entrapment of the occipital nerves is followed by lancinating pain in their territory. The intervening steps are not established for these nerves, and are deliberately not assumed to be the ephaptic mechanism demonstrated for cranial nerve roots.

Show evidence (1 reference)

PMID:39217283 SUPPORT INDIRECT Other

"Six, four, and one potential entrapment points were detected for the GON, TON, and LON, respectively."

Cadaveric dissection study establishing that the compression points relevant to these nerves are extracranial sites along their course rather than a root entry zone. Marked INDIRECT because it maps anatomy and does not show that entrapment at those points causes occipital neuralgia, and OTHER because it is a dissection study with no patients or cohort.

⬡

Pathograph

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

●

Phenotypes

Cardiovascular 1

Reflex Bradycardia and Cardiac Syncope During Attacks VERY_RARE HP:0001279

Show evidence (2 references)

PMID:27102416 SUPPORT Human Clinical

"Even more uncommon is the association between glossopharyngeal neuralgia and cardiac syncope. In these patients, the cardiovascular consequences may include bradycardia, hypotension and cardiac arrest."

Supports the association and names the cardiovascular consequences. This is a single case report, so it establishes that the phenomenon occurs rather than how often, which is why the frequency is recorded as VERY_RARE.

PMID:27102416 SUPPORT Human Clinical

"Multiple pauses including one lasting 14 s were noted on ambulatory ECG monitoring."

Objective conduction pauses on monitoring, which is what makes this a cardiac rather than a purely painful complication.

Constitutional 2

Concomitant Persistent Background Pain FREQUENT Chronic pain HP:0012532

Temporal: CHRONIC

Show evidence (2 references)

PMID:25231219 SUPPORT Human Clinical

"Notably, 78 (49%) had concomitant persistent pain in addition to paroxysmal stabbing pain."

Prospective series quantifying the fraction with a persistent pain component.

PMID:27306631 SUPPORT Human Clinical

"There is, however, compelling evidence that continuous and paroxysmal pain may improve independently after microvascular decompression, suggesting that the mechanisms responsible for the 2 pain components are distinct"

Supports the claim that the persistent component is mechanistically separate from the paroxysms.

Deep Ear Pain HP:0030766

Show evidence (1 reference)

PMID:39847207 SUPPORT Human Clinical

"NIN presents as a rare neuralgia of this nerve, causing deep ear pain, which may radiate to the auditory canal, auricle, mastoid, soft palate, temple, and angle of the jaw."

Defines the pain territory of this phenotype.

Other 6

Paroxysmal Lancinating Facial Pain OBLIGATE Trigeminal neuralgia HP:0100661

Temporal: RECURRENT

Show evidence (1 reference)

PMID:27306631 SUPPORT Human Clinical

"The paroxysms may last up to 2 minutes, but their duration is usually limited to a few seconds. Frequency of the pain attacks may range from 1 to over 50 a day."

Quantifies attack duration and frequency for this phenotype.

Unilateral Pain Distribution VERY_FREQUENT

Left unbound on purpose. This record is a laterality claim, and HPO has no term for it; the schema's `LateralityEnum` has no UNILATERAL value either. Binding HP:0033345 Neuralgia here would restate the pain concept already bound on the first phenotype without expressing the laterality, so the free-text `preferred_term` is kept instead.

Show evidence (1 reference)

PMID:27306631 SUPPORT Human Clinical

"Painful symptoms associated with TN are virtually always unilateral. Bilateral TN is very rare except for TN caused by multiple sclerosis (MS)."

Supports both the unilaterality and its exception in multiple sclerosis.

Trigger-Evoked Attacks VERY_FREQUENT

Deliberately left unbound. HP:0012533 Allodynia is the obvious candidate and is wrong: the source cited here separates the two explicitly, noting that confined trigger zones and the refractory period after an attack distinguish triggered neuralgia from mechanical allodynia. No HPO term expresses trigger-zone-evoked paroxysm, so a free-text `preferred_term` is kept rather than asserting allodynia.

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Therefore we propose that triggered pain qualifies as criterion supporting the diagnosis of clinically established TN"

Supports triggerability as a defining, diagnostically used feature.

PMID:27306631 SUPPORT Human Clinical

"Confined trigger zones and a common combination with brisk muscle contractions (tics) help distinguish triggered TN from allodynia in other conditions of neuropathic pain."

The source separating triggered neuralgia from allodynia, which is why no HPO term is bound here.

Sensory Deficit in the Affected Territory OCCASIONAL Hypoesthesia HP:0033748

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Clinical deficits of discriminatory sensory functions are highly suspicious of TN caused by a major underlying disease. They occurred in 25 out of 67 patients (37%) with TN secondary to tumors or MS."

Quoted as a contiguous pair so the referent of the pronoun sits inside the quote. Quantifies sensory deficit frequency in secondary disease, which is what makes it diagnostically useful.

PMID:25231219 SUPPORT Human Clinical

"Patients who had not undergone surgery for TN had sensory abnormalities in 35 (29%)."

Shows sensory abnormalities are not confined to secondary disease or to post-surgical patients.

Cranial Autonomic Features FREQUENT Increased tear production HP:0031731

Show evidence (3 references)

DOI:10.22514/jofph.2024.023 SUPPORT Human Clinical

"40% of all patients with craniofacial neuralgias had at least one autonomic feature."

Meta-analytic estimate of how often autonomic features accompany craniofacial neuralgia.

DOI:10.22514/jofph.2024.023 SUPPORT Human Clinical

"With trigeminal neuralgia, the most common autonomic feature was lacrimation, and the least common was nasal congestion."

Identifies lacrimation as the commonest autonomic accompaniment in trigeminal neuralgia, which is the phenotype term bound here.

PMID:25231219 SUPPORT Human Clinical

"Autonomic symptoms were present in 48 (31%)."

Independent prospective series giving a concordant frequency.

Occipital Scalp Pain Occipital neuralgia HP:0012318

Show evidence (1 reference)

PMID:24737457 SUPPORT Human Clinical

"Occipital pain is a common complaint amongst patients with headache, and the differential can include many primary headache disorders such as cervicogenic headache or migraine."

Supports both the location of the pain and the differential-diagnostic difficulty noted in the description.

🧬

Genetic Associations

C8B (Candidate-gene susceptibility association; not causative)

Gene: C8B hgnc:1353 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

DOI:10.1007/s12031-024-02263-x SUPPORT DIRECT Human Clinical

"Two SNPs corresponding to C8B rs706484 [odds ratio (OR) (95% confidence interval (CI)): 1.357 (1.158–1.590); p: 0.00016] and MFG-E8 rs2015495 [OR (95% CI): 1.313 (1.134–1.521); p: 0.00028] showed significant positive association with TN"

UK Biobank case-control association giving the effect size for this gene. The quoted sentence states the association itself, which is exactly what the SUSCEPTIBILITY relationship_type claims -- an association in one cohort, not a causal role.

DOI:10.1007/s12031-024-02263-x SUPPORT DIRECT Human Clinical

"The identified genetic variations may help explain why some individuals develop TN while others do not, indicating a potential genetic predisposition to the condition."

The authors' own framing, which is predisposition rather than causation -- the reason `relationship_type` here is SUSCEPTIBILITY.

MFGE8 (Candidate-gene susceptibility association; not causative)

Gene: MFGE8 hgnc:7036 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

DOI:10.1007/s12031-024-02263-x SUPPORT DIRECT Human Clinical

"Our findings suggest novel genetic associations between C8B, a key component of the complement system, and MFG-E8, which plays a role in regulating neuroinflammation, in relation to TN."

Names both genes and the proposed biology in the quoted sentence itself. The authors state a suggestion of association rather than an established mechanism, which is why this entry records susceptibility and does not wire either gene into the pathograph.

DOI:10.1007/s12031-024-02263-x SUPPORT DIRECT Human Clinical

"The study sample comprised of diagnosed TN cases (N = 555) and randomly matched controls (N = 6245) based on specific criteria."

The cohort size behind the association, recorded so the strength of the claim can be judged from the entry.

💊

Medical Actions

Carbamazepine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: carbamazepine CHEBI:3387

First-line pharmacotherapy. Stabilizes voltage-gated sodium channels in their inactivated state, which raises the threshold for the repetitive high-frequency firing that generates a paroxysm. Sedation, dizziness, ataxia, hyponatraemia, hepatic and haematologic toxicity, rash, and drug interactions require monitoring.

Mechanism Target:

INHIBITS Dysregulated Voltage-Gated Sodium Channel Expression — Sodium-channel blockade acts directly on the remodelled channels that underlie the lowered firing threshold, suppressing high-frequency discharge before it can synchronize into a paroxysm.

Show evidence (1 reference)

PMID:31908187 SUPPORT Human Clinical

"Their mechanism of action is a modulation of voltage-gated sodium channels, leading to a decrease in neuronal activity."

States the sodium-channel mechanism that connects this drug to the channel-dysregulation node.

Show evidence (1 reference)

PMID:30860637 SUPPORT Human Clinical

"For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice."

Guideline recommendation establishing first-line status.

Oxcarbazepine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: oxcarbazepine CHEBI:7824

First-line alternative to carbamazepine with the same sodium-channel mechanism and a generally more favourable interaction and tolerability profile, though hyponatraemia remains a concern.

Mechanism Target:

INHIBITS Dysregulated Voltage-Gated Sodium Channel Expression — Shares the sodium-channel-modulating mechanism of carbamazepine and acts on the same node.

Show evidence (1 reference)

PMID:31908187 SUPPORT Human Clinical

"The antiepileptic drugs carbamazepine and oxcarbazepine are the first-line pharmacological treatment for trigeminal neuralgia. Their mechanism of action is a modulation of voltage-gated sodium channels, leading to a decrease in neuronal activity."

Names oxcarbazepine and states its sodium-channel mechanism in the same quoted passage, so the mechanism claim stands on the quote itself.

Show evidence (1 reference)

PMID:30860637 SUPPORT Human Clinical

"For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice."

Guideline recommendation establishing first-line status alongside carbamazepine.

Second-Line and Add-On Anticonvulsant Therapy

Category: Therapeutic Action: Anticonvulsant Therapy NCIT:C64172

Agent: lamotrigine CHEBI:6367 gabapentin CHEBI:42797 pregabalin CHEBI:64356 baclofen CHEBI:2972

Lamotrigine, gabapentin, pregabalin, baclofen, and phenytoin are used alone or added to a first-line agent when it fails or is not tolerated. For glossopharyngeal neuralgia the same first-line-then-alternatives approach is applied, with gabapentin and eslicarbazepine acetate as the usual alternatives.

Show evidence (2 references)

PMID:30860637 SUPPORT Human Clinical

"Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy."

Guideline listing of the second-line and add-on agents named here.

DOI:10.52965/001c.36042 SUPPORT Human Clinical

"Conservatively, first-line management of GPN is carbamazepine, but gabapentin and eslicarbazepine acetate are suitable alternatives."

Supports the same drug strategy applying to the glossopharyngeal subtype.

Intravenous Therapy for Acute Exacerbation

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: fosphenytoin CHEBI:5165 lidocaine CHEBI:6456

Intravenous fosphenytoin or lidocaine for a crisis of uncontrolled attacks, where oral titration is too slow and the patient may be unable to eat or drink.

Show evidence (1 reference)

PMID:30860637 SUPPORT Human Clinical

"In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used."

Guideline recommendation for the acute crisis setting.

Microvascular Decompression

Category: Therapeutic Action: Neurosurgical Procedure NCIT:C15656

Posterior fossa craniotomy to interpose material between the offending vessel and the nerve root, leaving the nerve intact. It is the only cause-directed treatment and gives the most durable medication-free relief, but carries the risks of a posterior fossa operation. Recommended as first-line surgery in classical disease; where MRI shows no neurovascular contact, ablative procedures are preferred instead.

Mechanism Target:

INHIBITS Neurovascular Compression at the Nerve Root Entry Zone — Separating the vessel from the root removes the compressive lesion itself. The rapidity of relief argues that the immediate benefit comes from ending the focal distortion and separating the apposed demyelinated axons rather than from remyelination, which may instead be what sustains relief and what underlies spontaneous remission.

Show evidence (1 reference)

PMID:11701590 SUPPORT Human Clinical

"Decompression of the nerve root produces rapid relief of symptoms in most patients with vessel-associated trigeminal neuralgia, probably because the resulting separation of demyelinated axons and their release from focal distortion reduce the spontaneous generation of impulses and prevent their..."

Directly links the operation to reversal of the compression node and, through it, to suppression of ectopic generation and ephaptic spread.

Show evidence (4 references)

PMID:8598865 SUPPORT Human Clinical

"Ten years after surgery, 70 percent of the patients (as determined by Kaplan-Meier analysis) had excellent final results-that is, they were free of pain without medication for tic."

Long-term prospective follow-up of 1185 patients quantifying durable medication-free relief.

PMID:8598865 SUPPORT DIRECT Human Clinical

"Major complications included two deaths shortly after the operation (0.2 percent) and one brain-stem infarction (0.1 percent). Sixteen patients (1 percent) had ipsilateral hearing loss."

Records the operative risk that qualifies the benefit claim.

PMID:30860637 SUPPORT Human Clinical

"Microvascular decompression is recommended as first-line surgery in patients with classical TN."

Guideline recommendation establishing the place of this operation.

+ 1 more reference

Percutaneous Ablative Procedures

Category: Therapeutic Action: Radiofrequency Ablation NCIT:C15666

Radiofrequency thermocoagulation, balloon compression, or glycerol rhizolysis of the trigeminal ganglion. Preferred where imaging shows no neurovascular contact, and in older or higher-risk patients who would not tolerate a craniotomy. They trade pain control for sensory loss: facial numbness, dysaesthesia, corneal anaesthesia, masseter weakness, and rarely anaesthesia dolorosa. Note that the bound `treatment_term` names radiofrequency ablation specifically; NCIT has no clinical-action term covering the balloon-compression and glycerol-rhizolysis alternatives grouped here, so the binding is narrower than this entry.

Mechanism Target:

INHIBITS Ectopic Discharge and Ephaptic Cross-Excitation — Unlike decompression, these procedures do not remove the cause; they lesion the conducting pathway so that ectopic and ephaptically spread activity cannot reach central pathways. The sensory deficit they produce is the direct cost of that non-selective approach.

Show evidence (1 reference)

PMID:30860637 SUPPORT INDIRECT Human Clinical

"Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact."

Supports the indication for these procedures. Marked INDIRECT because the guideline states when to use them, not the conduction-block mechanism asserted in this link's description.

Show evidence (3 references)

DOI:10.1186/s12883-023-03415-z SUPPORT Human Clinical

"At 48 weeks, the complete remission rate was significantly higher (P < 0.05) in the MVD group than in PRT group. No significant difference in adverse reactions was observed between the two groups."

Head-to-head comparison in the glossopharyngeal subtype showing that the cause-directed operation buys more complete remission than ablation, which is the trade-off this entry models as decompression acting on the compression node and ablation acting only on the discharge node.

DOI:10.1186/s12883-023-03415-z SUPPORT DIRECT Human Clinical

"The length of hospital stay, operative time, and cost were significantly higher (P < 0.05) in the MVD group than in the PRT group."

The countervailing cost of the more definitive operation, which is why ablation remains the option for higher-risk patients. The quoted sentence states those costs directly. Note the design is a retrospective single-centre comparison, so the size of the difference should not be read as a general estimate.

PMID:30860637 SUPPORT Human Clinical

"No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN."

Records the guideline's explicit equipoise between ablative options in idiopathic disease.

Stereotactic Radiosurgery

Category: Therapeutic Action: Radiosurgery NCIT:C15696

Focused radiation to the trigeminal root, avoiding open surgery at the cost of delayed onset of relief and a meaningful recurrence rate. Suitable where craniotomy is not appropriate.

Show evidence (4 references)

PMID:37144649 SUPPORT Human Clinical

"The initial pain relief rate was 85%, with a median period of 25 (range, 1-90) days. At the final follow-up, 62.5% of patients had adequate pain relief."

163-patient series quantifying both the delayed onset of relief and its attrition over follow-up, which are the two properties this treatment's description turns on.

PMID:37144649 SUPPORT INDIRECT Human Clinical

"The predicted adequate pain relief rates at the 3rd and 6th month and 1st, 3rd, 5th, and 7th year were 84%, 79%, 76%, 67%, 59%, and 55%, respectively."

The declining curve behind the recurrence-risk claim. Marked INDIRECT because these are model-predicted rather than directly observed rates.

PMID:38385643 SUPPORT DIRECT Human Clinical

"Gamma Knife radiosurgery is a non-invasive, efficacious treatment option for idiopathic GPN, offering short- and long-term relief without permanent complications."

Extends the option to the glossopharyngeal subtype, which the quoted conclusion asserts directly. It rests on eight patients, so it establishes that the option is used and reported rather than a general efficacy rate.

+ 1 more reference

Botulinum Toxin Type A Injection

Category: Therapeutic Action: Botulinum Toxin Therapy NCIT:C157775

Agent: onabotulinumtoxinA CHEBI:3160

Off-label option for refractory disease, injected into the painful territory. Listed by guideline among the agents that may be used alone or as add-on therapy; meta-analysis of randomized trials supports a treatment effect.

Show evidence (2 references)

PMID:27377706 SUPPORT Human Clinical

"Despite limited data, our results suggest that BTX-A may be an effective and safe treatment option for patients with TN."

Meta-analysis of four randomized trials concluding a probable treatment effect. The authors' own hedge on the limited data is kept in the quote rather than trimmed away.

PMID:30860637 SUPPORT Human Clinical

"Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy."

Guideline placement of botulinum toxin among add-on options.

Occipital Nerve Block

Category: Therapeutic Action: Occipital Nerve Block NCIT:C157940

Local anaesthetic with or without corticosteroid injected at the greater occipital nerve. First-line minimally invasive intervention for occipital neuralgia and used diagnostically, though relief is often short-lived and blocks also relieve migraine, so a response is not specific.

Mechanism Target:

INHIBITS Extracranial Entrapment of the Occipital Nerves — The block is delivered at the anatomical entrapment points along the nerve's extracranial course, which is why the procedure targets this node rather than the root-entry-zone node.

Show evidence (1 reference)

PMID:39217283 SUPPORT INDIRECT Other

"we aimed to investigate the potential compression points of the greater occipital nerve (GON), third occipital nerve (TON), and lesser occipital nerve (LON) which are targeted to block in occipital nerve blocks"

Establishes that the compression points are the anatomical targets of the block. Marked INDIRECT because it is a cadaveric dissection study and reports no clinical outcomes.

Show evidence (2 references)

PMID:34287719 SUPPORT Human Clinical

"The occipital nerve block is considered the first line in a minimally invasive intervention, but the duration of relief may be short term."

Supports both the first-line placement and the durability caveat.

PMID:24737457 SUPPORT DIRECT Human Clinical

"However, nerve blocks are also effective in migraine headache and misdiagnosis can result in a false positive."

Records the limit on using a block response as a diagnostic test.

Psychological and Nursing Support

Category: Counseling / Informational Action: Supportive Care NCIT:C15747

Guideline-recommended alongside medical and surgical management. The recurrent excruciating pain, impaired eating and speech, and medication burden carry a substantial psychiatric and functional cost that drug and procedural treatment do not address on their own.

Show evidence (1 reference)

PMID:30860637 SUPPORT Human Clinical

"In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support."

Direct guideline recommendation for this component of care.

🌍

Environmental Factors

Chronic arterial hypertension

Deliberately left without an `exposure_term`. ECTO was searched and carries only exposure-to-antihypertensive-agent concepts (ECTO:2000001, ECTO:9001744), which describe treatment rather than the hypertensive state itself; XCO likewise offers only `antihypertensive agent`. Binding either would assert the opposite of the claim made here. Note also that hypertension is a host physiological state rather than an external exposure, and is placed in `environmental:` because that is where this schema carries modifiable, non-genetic risk factors.

Hypertension is associated with an increased subsequent risk of trigeminal neuralgia in population data. The proposed link is through arterial elongation, tortuosity, and stiffening, which make a compressive vascular loop at the root entry zone more likely — an association, not a demonstrated causal pathway.

Show evidence (1 reference)

PMID:2301931 SUPPORT Human Clinical

"This study indicates an elevated relative risk associated with hypertension (both overall and among women in the cohort)."

Independent population-based cohort reporting the same association.

Mechanism Target:

PREDISPOSES Neurovascular Compression at the Nerve Root Entry Zone — Hypertensive vascular remodelling is the proposed route by which hypertension raises the probability of a compressive arterial loop contacting the nerve root. The intervening steps have not been demonstrated.

Show evidence (1 reference)

PMID:21998318 SUPPORT INDIRECT Human Clinical

"This study shows a significantly increased risk of developing TN after hypertension. Further studies are needed to elucidate the underlying mechanism of the association between hypertension and TN."

Population cohort of 138,492 hypertensive persons establishing the temporal association. Marked INDIRECT because the authors state explicitly that the underlying mechanism is not established, so this supports the risk relationship but not the vascular-remodelling route this link proposes.

🔬

Diagnosis

MRI of the posterior fossa and cranial nerves

High-resolution MRI is required rather than optional, because no clinical feature reliably excludes a secondary cause. It serves two purposes at once: excluding tumour, multiple sclerosis, aneurysm, and vascular malformation, and grading the degree of neurovascular contact to inform whether and when to refer for decompression. Demonstrating contact does not confirm the diagnosis.

Show evidence (2 references)

PMID:30860637 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN."

Guideline recommendation establishing MRI as a required part of the work-up and the reason for it.

PMID:30860637 SUPPORT Human Clinical

"demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression."

Supports the stated limit on how imaging findings should be used.

Trigeminal reflex recording

Electrophysiological alternative when MRI cannot be performed. Reflex abnormalities discriminate secondary from primary disease with accuracy comparable to MRI.

Show evidence (1 reference)

PMID:27306631 SUPPORT Human Clinical

"Reflex abnormalities achieve a sensitivity of 94% and specificity of 87% to identify secondary TN, comparable to the diagnostic accuracy of MRI."

Gives the diagnostic performance figures that justify this as an MRI substitute.

📈

Progression

Recurrent active periods separated by complete remissions

Trigeminal

The course is remitting rather than steadily progressive, which sets this disease apart from most neuropathic pain and matters for judging whether a treatment worked. Remissions lasting weeks to years occur in a majority of patients, so spontaneous improvement is a live confounder in any uncontrolled treatment series.

Show evidence (2 references)

PMID:27306631 SUPPORT Human Clinical

"Unlike other forms of neuropathic pain, TN enters into periods of complete remission in up to 63% of patients."

Quantifies the remitting course this phase describes.

PMID:27306631 SUPPORT Human Clinical

"These periods may last from weeks to years."

Gives the duration range of the remissions.

Attack frequency and duration over the course of illness

Trigeminal

Recorded because the intuitive model is wrong. Attacks were long assumed to grow more frequent and longer as the disease went on; a 200-patient study of classical disease found no such relationship with disease duration. This entry therefore does not model a severity-escalation edge, and a curator should not add one without evidence.

Show evidence (1 reference)

PMID:27306631 SUPPORT Human Clinical

"Refuting earlier assumptions,7 a recent study in 200 patients with classical TN did not find evidence supporting an increase in frequency or duration of the pain paroxysms with the disease duration."

Directly refutes progressive escalation of attack frequency or duration, which is what this phase records.

📊

Prevalence

Rochester, Minnesota residents, 1945-1984

Annual Incidence 4.3 per 100,000 1–9 per 100,000 Trigeminal

Crude annual incidence, both sexes combined; age-adjusted rate higher in women (5.9) than men (3.4).

Show evidence (1 reference)

PMID:2301931 SUPPORT Human Clinical

"The overall crude incidence rate of trigeminal neuralgia per 100,000 population in Rochester, Minnesota, for 1945 through 1984 was 4.3 for both sexes combined."

Population-based record-linkage cohort giving the classic annual incidence figure.

Women in three observational population-based adult samples

Point Prevalence 3.0–30.0 per 100,000 1–9 per 10,000 Trigeminal

Systematic review of population-based prevalence studies; reported as 0.03% to 0.3%, converted here to 3-30 per 100,000. The wide band reflects only three includable studies. Note that the reported range straddles a class boundary -- the low end falls in BAND_1_9_PER_100000 and the high end in BAND_1_5_PER_10000; the class recorded here is the one the repository's midpoint rule (scripts/migrate_prevalence.py) yields for 3-30.

Show evidence (1 reference)

PMID:27017183 SUPPORT Human Clinical

"This review identified a higher prevalence of TN in women, ranging from 0.03% (95% confidence interval [CI], 0.01-0.08) to 0.3% (95% CI, 0.16-0.55)."

Supplies the population prevalence range and the female preponderance.

Rochester, Minnesota residents, 1945-1984

Annual Incidence 0.7 per 100,000 1–9 per 1,000,000 Glossopharyngeal

Crude annual incidence, both sexes combined; roughly one sixth the trigeminal rate in the same cohort.

Show evidence (1 reference)

PMID:1798429 SUPPORT Human Clinical

"The annual crude incidence rate of glossopharyngeal neuralgia per 100,000 population in Rochester, Minn., for 1945 through 1984, was 0.7 for both sexes combined, suggesting that glossopharyngeal neuralgia is a rare disease."

Population-based incidence for the glossopharyngeal subtype from the same cohort as the trigeminal figure.

Patients with multiple sclerosis (19 studies, 30,348 patients)

Period Prevalence 3400.0 per 100,000 >1 in 1,000 Trigeminal

Prevalence of trigeminal neuralgia within an MS population, not a general population estimate; quantifies the secondary-aetiology burden.

Show evidence (1 reference)

PMID:34986455 SUPPORT Human Clinical

"Pooled overall TN prevalence among 19 studies and 30,348 MS patients was estimated as 3.4% (95% CI: 1.5%-5.9%)"

Meta-analytic estimate of trigeminal neuralgia frequency among people with multiple sclerosis.

⚖️

Clinical Burden

High

Life expectancy is not reduced, but morbidity is severe and largely psychiatric and functional rather than structural. Pain that is provoked by eating, speaking, and washing attacks the activities that make ordinary life possible, and the downstream psychiatric risk is large and measurable rather than impressionistic: roughly a threefold increase in newly diagnosed depressive, anxiety, and sleep disorders in a nationwide cohort. The glossopharyngeal subtype adds a small but real risk of cardiac syncope.

Show evidence (2 references)

PMID:26174508 SUPPORT Human Clinical

"The adjusted hazard ratio (aHR) of depressive disorder, anxiety disorder and sleep disorder in subjects with TN was higher than that of the controls during the follow-up [aHR: 2.85 (95% confidence interval: 2.11-3.85), aHR: 2.98 (95% confidence interval: 2.12-4.18) and aHR: 2.17 (95% confidence..."

Nationwide cohort of 3273 patients quantifying the psychiatric burden that drives the HIGH assessment.

PMID:26174508 SUPPORT INDIRECT Human Clinical

"TN might increase the risk of subsequent newly diagnosed depressive disorder, anxiety disorder, and sleep disorder, but not schizophrenia or bipolar disorder."

The authors' own hedged conclusion, kept rather than trimmed. It also records the negative result for schizophrenia and bipolar disorder, so the burden claim is not read more broadly than the data support.

🔬

Clinical Trials

NCT06620172 NOT_APPLICABLE RECRUITING

Randomized comparison of CT-guided versus fluoroscopy-guided trigeminal ganglion radiofrequency thermocoagulation in idiopathic trigeminal neuralgia, with pain relief, medication consumption, and adverse events followed to six months.

Show evidence (1 reference)

clinicaltrials:NCT06620172 SUPPORT Human Clinical

"Does CT-guided TG-RFT provide better pain relief compared to fluoroscopy-guided TG-RFT?"

The trial's primary question, which concerns how the ablative procedure curated here is targeted.

NCT05491915 NOT_APPLICABLE ACTIVE_NOT_RECRUITING

Multicenter case series of 60-day percutaneous peripheral nerve stimulation for occipital neuralgia and cervicogenic headache, relevant to the occipital subtype where refractory disease has few durable options.

Show evidence (1 reference)

clinicaltrials:NCT05491915 SUPPORT Human Clinical

"The purpose of this study is to learn if pain can be relieved by delivering small amounts of electricity (called "electrical stimulation") to the nerves at the top of the neck."

Describes stimulation of the upper cervical nerves, which are the nerves the occipital subtype involves. The registry title names occipital neuralgia as the study population.

🐁

Animal Models

Rat infraorbital nerve chronic constriction injury

A ligature is placed around the infraorbital branch of the trigeminal nerve, producing a sustained drop in facial mechanical threshold and a measurable change in trigeminal ganglion sodium-channel expression. It is the source of the subunit-level detail in this entry's channel node, and it is included here explicitly so that the model's limits are attached to the graph rather than left in prose.

Species

Rat

Genotype

Wild-type Sprague-Dawley

Publication

PMID:27327156

Pathograph links

Dysregulated Voltage-Gated Sodium Channel Expression partially recapitulates fidelity: low The model does reproduce injury-driven remodelling of voltage-gated sodium channel expression in trigeminal ganglion neurons, which is the claim this node makes.

Limitations: It injures a distal peripheral branch, whereas the human lesion is focal demyelination of the central, oligodendrocyte-myelinated segment of the root -- a different site and a different myelinating cell. The subunit pattern it reports has not been confirmed in human trigeminal ganglion.

Readouts

Nav1.3 transcript and protein in trigeminal ganglion

Direction: INCREASED

Interpretation: Upregulation of a channel subunit associated with neuronal hyperexcitability after injury.

Show evidence (1 reference)

PMID:27327156 SUPPORT Model Organism

Reports the measured direction of change for each subunit, including the Nav1.3 increase this readout records.

Show evidence (1 reference)

PMID:27327156 SUPPORT INDIRECT Model Organism

"Our findings suggest that VGSC may participate in the regulation of TN."

The authors' own claim for the model is a suggestion that these channels participate, which is the strength this link is graded at.

Paroxysmal Neuralgiform Pain fails to recapitulate fidelity: low The model does not reproduce the defining clinical phenotype. Human cranial neuralgia is brief, trigger-evoked, and remitting; the model produces a sustained lowering of mechanical threshold over weeks.

Limitations: There is no trigger zone, no paroxysm, no refractory period, and no remission in this preparation, so it cannot be used to test claims about the paroxysmal character of the disease. Devor and colleagues state outright that no satisfactory animal model of trigeminal neuralgia exists.

Readouts

Facial mechanical pain threshold

Direction: DECREASED

Interpretation: A sustained threshold drop lasting weeks, which is a different behavioural pattern from the brief evoked paroxysms it is meant to model.

Show evidence (1 reference)

PMID:27327156 SUPPORT Model Organism

"Behavioral tests showed that the mechanical pain threshold decreased significantly 4-42 days after surgery and reached the lowest observed value by day 12."

The measured time course, which is sustained over weeks rather than paroxysmal.

Show evidence (1 reference)

PMID:11803297 SUPPORT Other

"There are no satisfactory animal models of trigeminal neuralgia, and it is difficult to obtain essential data from patients."

Substantiates the negative claim that no available animal model reproduces the human disease phenotype.

Show evidence (1 reference)

PMID:27327156 SUPPORT Model Organism

"We used the infraorbital nerve-chronic constriction injury model of TN in the rat."

Establishes the model preparation this entry describes.

{ }

Source YAML

click to show

name: Cranial Neuralgia
creation_date: '2026-08-28T00:00:00Z'
category: Complex
categories:
- Neurological
- Neuropathic Pain
parents:
- neuralgia
- cranial nerve neuropathy
synonyms:
- cranial nerve neuralgia
- craniofacial neuralgia
disease_term:
  preferred_term: cranial neuralgia
  term:
    id: MONDO:0016374
    label: cranial neuralgia
description: >-
  Cranial neuralgia is paroxysmal, severe, lancinating pain confined to the
  sensory territory of a cranial (or, by clinical convention, an upper cervical)
  nerve, characteristically provoked by innocuous stimulation of a trigger zone.
  In the nerve-defined forms that dominate the category — trigeminal neuralgia
  by a wide margin, then glossopharyngeal and nervus intermedius neuralgia — the
  best-supported mechanism is chronic pulsatile compression of the nerve root by
  an overlying artery close to its entry into the brainstem. That compression
  produces focal demyelination and juxtaposition of bare axons, which favours
  ectopic impulse generation and ephaptic cross-talk between large tactile
  afferents and nociceptive fibres; synchronized high-frequency afterdischarge
  is then experienced as an abrupt shock-like paroxysm. The same demyelinating
  lesion is reached by other routes in secondary disease, most often a
  pontine multiple sclerosis plaque or a posterior fossa tumour compressing the
  root. Sodium-channel-blocking anticonvulsants (carbamazepine, oxcarbazepine)
  suppress the high-frequency firing and are first-line; microvascular
  decompression removes the compressive lesion itself and gives the most durable
  medication-free relief.
notes: >-
  Concept decision (issue #9605). This is curated as a single Disease entry with
  nerve-defined `has_subtypes` rather than as a `kb/groupings/` union, because
  the classical forms share one mechanistic spine node-for-node: neurovascular
  compression at the root entry zone -> focal demyelination -> ectopic discharge
  and ephaptic cross-excitation -> paroxysmal lancinating pain, with the same
  first-line drug class and the same cause-directed operation. Love and Coakham
  (PMID:11701590) make that argument explicitly, concluding that demyelination
  and ephaptic spread underlie most or all of the vascular-compression cranial
  nerve hyperactivity syndromes. What varies between subtypes is which nerve
  carries the lesion, and therefore the pain territory, the offending vessel,
  and the trigger manoeuvre — anatomical substitution on a conserved graph,
  which is the same pattern the mechanism-module convention treats as
  conformance rather than as a union of distinct diseases. Szmyd and colleagues
  (PMID:35860499), a 2022 systematic review of 63 papers on the neurovascular
  compression syndromes, reach the same grouping two decades after Love and
  Coakham and explicitly include geniculate (nervus intermedius) neuralgia in
  it, which matters because that is the thinnest subtype curated here.
  .
  Occipital neuralgia is the deliberate exception and is curated as a subtype
  with a stated caveat rather than silently folded in. It is grouped here by
  ICHD-3 clinical convention and by the MONDO/HPO neuralgia hierarchy, but the
  greater and lesser occipital nerves are branches of the C2-C3 dorsal rami, not
  cranial nerves, and the compression points described anatomically are
  extracranial sites along the nerve's course through muscle and beside the
  occipital artery (PMID:39217283) rather than a brainstem root entry zone. Its
  pathophysiology node is therefore kept separate from the root-entry-zone node
  and does not claim the ephaptic mechanism. Note also that MONDO:0016374 does
  not itself have occipital neuralgia among its descendants.
  .
  The falcon deep-research report generated for this entry argued the opposite
  case — that cranial neuralgia is "an umbrella clinical category, not one
  etiologically uniform disease" and that the entities should be represented
  separately. That reading is recorded here rather than discarded: it is correct
  about epidemiology and about procedure selection, which genuinely do not
  transfer between subtypes. That is why every `prevalence` record here carries
  an explicit `subtype:` rather than being stated at the root, and why the
  treatment entries name which subtype each option applies to in their own
  prose -- `Treatment` has no `subtype` slot, so that distinction cannot be
  made structurally the way it can for prevalence and phenotypes. It is the
  mechanism, not the clinical management, that is shared. If a future
  curator finds the per-subtype pathographs diverging further, splitting
  trigeminal neuralgia (MONDO:0008599) into its own entry and converting this
  one to a grouping would be the right move. The `stubs/Trigeminal_Neuralgia.yaml`
  queue entry is closed by this PR because MONDO:0008599 is now covered as a
  `has_subtypes` entry here; re-nominating it is the route if that split is
  later wanted.
  .
  On genetics: there is no Mendelian basis here and no gene is necessary or
  sufficient, so the `genetic:` section carries susceptibility signals only. The
  two entries there (C8B, MFGE8) come from a single unreplicated candidate-gene
  analysis in UK Biobank with small effect sizes and no genome-wide correction.
  They are recorded because they are the best available human genetic evidence
  and because a reader should be able to see the question was considered rather
  than skipped -- not because they carry mechanistic weight. Neither is wired
  into the pathograph: the proposed biology is complement activation and
  neuroinflammation, which this entry does not model, and whether that
  neuroinflammatory signal drives the disease or simply follows nerve injury is
  recorded as an open discussion rather than assumed either way.
definitions:
- name: Paroxysmal cranial neuralgia pain phenotype
  definition_type: OTHER
  description: >-
    Recurrent brief shock-like pain restricted to the distribution of a single
    cranial nerve, of abrupt onset and termination, usually unilateral.
  scope: Applies across the nerve-defined subtypes; does not by itself distinguish classical from secondary aetiology.
  evidence:
  - reference: PMID:38575268
    reference_title: Trigeminal and Glossopharyngeal Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trigeminal neuralgia and glossopharyngeal neuralgia are craniofacial pain syndromes characterized by recurrent brief shock-like pains in the distributions of their respective cranial nerves."
    explanation: States the shared paroxysmal, nerve-territory-confined pain phenotype that defines the category.
- name: Aetiological classification of trigeminal neuralgia
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Three-category aetiological grading: classical (imaging shows vascular
    compression with morphological change of the nerve root), secondary (an
    identifiable underlying neurological disease), and idiopathic (no cause
    found).
  scope: >-
    Developed for trigeminal neuralgia and extended by analogy to the other
    cranial neuralgias, where it has not been separately validated.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic."
    explanation: Gives the three aetiological categories verbatim as proposed by the classification working group.
  - reference: PMID:39847207
    reference_title: Nervus Intermedius Neuralgia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like trigeminal neuralgia, NIN can be divided into classic, idiopathic, secondary, or painful neuropathy."
    explanation: Supports extension of the same scheme to nervus intermedius neuralgia, though this review notes the evidence base for that subtype is thin.
has_subtypes:
- name: Trigeminal
  display_name: Trigeminal Neuralgia (CN V)
  classification: affected_nerve
  description: >-
    By far the commonest cranial neuralgia. Pain is confined to one or more
    divisions of the trigeminal nerve, most often the maxillary and mandibular
    divisions, and is almost always unilateral. Severe neurovascular contact at
    the trigeminal root entry zone, usually arterial, is the dominant classical
    aetiology.
  subtype_term:
    preferred_term: trigeminal neuralgia
    term:
      id: MONDO:0008599
      label: trigeminal neuralgia
  locations:
  - preferred_term: trigeminal nerve root
    term:
      id: UBERON:0004673
      label: trigeminal nerve root
  evidence:
  - reference: PMID:25231219
    reference_title: Trigeminal neuralgia--a prospective systematic study of clinical characteristics in 158 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It affected solely the second and/or third trigeminal branch in 109 (69%) while the first branch alone was affected in only 7 (4%)."
    explanation: Prospective series quantifies the divisional distribution that characterises this subtype.
- name: Glossopharyngeal
  display_name: Glossopharyngeal Neuralgia (CN IX)
  classification: affected_nerve
  description: >-
    Paroxysmal pain in the posterior tongue, tonsillar fossa, pharynx, and deep
    ear, triggered by swallowing, talking, or coughing. Compression of the
    glossopharyngeal and vagal rootlets near the medulla is the usual classical
    cause. Because the glossopharyngeal nerve carries the carotid-sinus afferent
    limb, attacks can recruit vagal reflex arcs and produce bradycardia,
    hypotension, and cardiac syncope -- rare, but the one way a cranial
    neuralgia becomes immediately dangerous.
  subtype_term:
    preferred_term: glossopharyngeal neuralgia
    term:
      id: MONDO:0016372
      label: glossopharyngeal neuralgia
  locations:
  - preferred_term: glossopharyngeal nerve
    term:
      id: UBERON:0001649
      label: glossopharyngeal nerve
  evidence:
  - reference: PMID:28263933
    reference_title: "Microvascular Decompression for Glossopharyngeal Neuralgia: Long-Term Follow-Up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classic GPN is usually caused by pulsatile neurovascular compression of the glossopharyngeal and vagus rootlets."
    explanation: Operative series identifies rootlet compression as the usual classical aetiology of this subtype.
- name: Nervus Intermedius
  display_name: Nervus Intermedius (Geniculate) Neuralgia (CN VII sensory root)
  classification: affected_nerve
  description: >-
    A rare neuralgia of the sensory branch of the facial nerve, producing deep
    ear pain that may radiate to the auditory canal, auricle, mastoid, soft
    palate, temple, and angle of the jaw. Compression by the anterior inferior
    cerebellar artery is the most commonly described cause. Diagnosis is
    confounded by overlap with trigeminal and glossopharyngeal territory.
  locations:
  - preferred_term: sensory root of facial nerve
    term:
      id: UBERON:0001699
      label: sensory root of facial nerve
  evidence:
  - reference: PMID:39847207
    reference_title: Nervus Intermedius Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NIN presents as a rare neuralgia of this nerve, causing deep ear pain, which may radiate to the auditory canal, auricle, mastoid, soft palate, temple, and angle of the jaw."
    explanation: Defines the pain territory of this subtype.
  - reference: PMID:39847207
    reference_title: Nervus Intermedius Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurovascular compression involving the anterior inferior cerebellar artery is the most common etiology described"
    explanation: Identifies the offending vessel for the classical form of this subtype.
  - reference: PMID:30095334
    reference_title: Nervus intermedius and the surgical management of geniculate neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Geniculate neuralgia (GN) is an uncommon craniofacial pain syndrome attributable to nervus intermedius (NI) dysfunction."
    explanation: Surgical series defining the subtype by the nerve involved, which is the axis this entry's subtypes are cut along.
  - reference: PMID:30095334
    reference_title: Nervus intermedius and the surgical management of geniculate neuralgia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis and treatment can be challenging, due to the complex nature of ear sensory innervation, resulting in clinical overlap with trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN)."
    explanation: >-
      Substantiates the diagnostic-overlap caveat in this subtype's description,
      which the quoted sentence asserts outright. It reports the overlap as a
      clinical difficulty rather than quantifying misdiagnosis, so the entry
      does not put a number on it.
  review_notes: >-
    No `subtype_term`. MONDO was searched for "nervus intermedius", "geniculate
    neuralgia", and the descendants of MONDO:0016374 (cranial neuralgia), which
    are facial neuralgia, trigeminal neuralgia, glossopharyngeal neuralgia, and
    combined hyperactive dysfunction syndrome of the cranial nerves. No term for
    this concept exists, so the subtype is left unbound rather than bound to a
    broader parent that would not identify it.
- name: Occipital
  display_name: Occipital Neuralgia (greater, lesser, and third occipital nerves)
  classification: affected_nerve
  description: >-
    Paroxysmal lancinating pain in the distribution of the greater, lesser, or
    third occipital nerves over the posterior scalp. Included here by ICHD-3
    clinical convention and by the HPO neuralgia hierarchy, but mechanistically
    the outlier of this entry: these are branches of the C2-C3 dorsal rami
    rather than cranial nerves, and the described compression points lie
    extracranially along the nerve's course, not at a brainstem root entry
    zone. See the entry-level notes.
  review_notes: >-
    No `subtype_term`. MONDO has no occipital neuralgia term and, consistent
    with the anatomical point above, occipital neuralgia is not among the
    descendants of MONDO:0016374. HP:0012318 Occipital neuralgia exists and is
    used on this subtype's phenotype record, but `subtype_term` is bound to the
    DiseaseOrSubtypeTerm enum, which an HP term is not a member of, so it cannot
    be used here.
  evidence:
  - reference: PMID:24737457
    reference_title: Occipital neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occipital neuralgia is an uncommon cause of occipital pain characterized by paroxysmal lancinating pain in the distribution of the greater, lesser or third occipital nerves."
    explanation: Establishes the pain character and nerve territory that place this alongside the cranial neuralgias.
prevalence:
- subtype: Trigeminal
  population: Rochester, Minnesota residents, 1945-1984
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 4.3
  notes: Crude annual incidence, both sexes combined; age-adjusted rate higher in women (5.9) than men (3.4).
  evidence:
  - reference: PMID:2301931
    reference_title: "Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945-1984."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall crude incidence rate of trigeminal neuralgia per 100,000 population in Rochester, Minnesota, for 1945 through 1984 was 4.3 for both sexes combined."
    explanation: Population-based record-linkage cohort giving the classic annual incidence figure.
- subtype: Trigeminal
  population: Women in three observational population-based adult samples
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 3.0
  rate_high: 30.0
  notes: >-
    Systematic review of population-based prevalence studies; reported as 0.03%
    to 0.3%, converted here to 3-30 per 100,000. The wide band reflects only
    three includable studies. Note that the reported range straddles a class
    boundary -- the low end falls in BAND_1_9_PER_100000 and the high end in
    BAND_1_5_PER_10000; the class recorded here is the one the repository's
    midpoint rule (scripts/migrate_prevalence.py) yields for 3-30.
  evidence:
  - reference: PMID:27017183
    reference_title: "Prevalence of trigeminal neuralgia: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review identified a higher prevalence of TN in women, ranging from 0.03% (95% confidence interval [CI], 0.01-0.08) to 0.3% (95% CI, 0.16-0.55)."
    explanation: Supplies the population prevalence range and the female preponderance.
- subtype: Glossopharyngeal
  population: Rochester, Minnesota residents, 1945-1984
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.7
  notes: Crude annual incidence, both sexes combined; roughly one sixth the trigeminal rate in the same cohort.
  evidence:
  - reference: PMID:1798429
    reference_title: "Incidence and clinical features of glossopharyngeal neuralgia, Rochester, Minnesota, 1945-1984."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The annual crude incidence rate of glossopharyngeal neuralgia per 100,000 population in Rochester, Minn., for 1945 through 1984, was 0.7 for both sexes combined, suggesting that glossopharyngeal neuralgia is a rare disease."
    explanation: Population-based incidence for the glossopharyngeal subtype from the same cohort as the trigeminal figure.
- subtype: Trigeminal
  population: Patients with multiple sclerosis (19 studies, 30,348 patients)
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3400.0
  notes: >-
    Prevalence of trigeminal neuralgia within an MS population, not a general
    population estimate; quantifies the secondary-aetiology burden.
  evidence:
  - reference: PMID:34986455
    reference_title: "Prevalence of trigeminal neuralgia in multiple sclerosis: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pooled overall TN prevalence among 19 studies and 30,348 MS patients was estimated as 3.4% (95% CI: 1.5%-5.9%)"
    explanation: Meta-analytic estimate of trigeminal neuralgia frequency among people with multiple sclerosis.
progression:
- phase: Recurrent active periods separated by complete remissions
  subtype: Trigeminal
  notes: >-
    The course is remitting rather than steadily progressive, which sets this
    disease apart from most neuropathic pain and matters for judging whether a
    treatment worked. Remissions lasting weeks to years occur in a majority of
    patients, so spontaneous improvement is a live confounder in any
    uncontrolled treatment series.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike other forms of neuropathic pain, TN enters into periods of complete remission in up to 63% of patients."
    explanation: Quantifies the remitting course this phase describes.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These periods may last from weeks to years."
    explanation: Gives the duration range of the remissions.
- phase: Attack frequency and duration over the course of illness
  subtype: Trigeminal
  notes: >-
    Recorded because the intuitive model is wrong. Attacks were long assumed to
    grow more frequent and longer as the disease went on; a 200-patient study of
    classical disease found no such relationship with disease duration. This
    entry therefore does not model a severity-escalation edge, and a curator
    should not add one without evidence.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Refuting earlier assumptions,7 a recent study in 200 patients with classical TN did not find evidence supporting an increase in frequency or duration of the pain paroxysms with the disease duration."
    explanation: Directly refutes progressive escalation of attack frequency or duration, which is what this phase records.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Life expectancy is not reduced, but morbidity is severe and largely
    psychiatric and functional rather than structural. Pain that is provoked by
    eating, speaking, and washing attacks the activities that make ordinary life
    possible, and the downstream psychiatric risk is large and measurable rather
    than impressionistic: roughly a threefold increase in newly diagnosed
    depressive, anxiety, and sleep disorders in a nationwide cohort. The
    glossopharyngeal subtype adds a small but real risk of cardiac syncope.
  evidence:
  - reference: PMID:26174508
    reference_title: "Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The adjusted hazard ratio (aHR) of depressive disorder, anxiety disorder and sleep disorder in subjects with TN was higher than that of the controls during the follow-up [aHR: 2.85 (95% confidence interval: 2.11-3.85), aHR: 2.98 (95% confidence interval: 2.12-4.18) and aHR: 2.17 (95% confidence interval: 1.48-3.19), respectively]."
    explanation: Nationwide cohort of 3273 patients quantifying the psychiatric burden that drives the HIGH assessment.
  - reference: PMID:26174508
    reference_title: "Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "TN might increase the risk of subsequent newly diagnosed depressive disorder, anxiety disorder, and sleep disorder, but not schizophrenia or bipolar disorder."
    explanation: >-
      The authors' own hedged conclusion, kept rather than trimmed. It also
      records the negative result for schizophrenia and bipolar disorder, so the
      burden claim is not read more broadly than the data support.
pathophysiology:
- name: Neurovascular Compression at the Nerve Root Entry Zone
  role: trigger
  biological_scale: TISSUE
  description: >-
    An arterial loop, less often a vein, contacts the sensory nerve root close
    to its entry into the brainstem and indents, displaces, or flattens it.
    Contact alone is common on asymptomatic nerves and is not sufficient; it is
    the morphological change — displacement or atrophy — that is specific to the
    symptomatic side, and its location at the root entry zone that carries the
    diagnostic weight. The compression is pulsatile, so the mechanical insult is
    delivered with every arterial cycle over years.
  locations:
  - preferred_term: trigeminal nerve root
    term:
      id: UBERON:0004673
      label: trigeminal nerve root
  - preferred_term: superior cerebellar artery
    term:
      id: UBERON:0001635
      label: superior cerebellar artery
  notes: >-
    No `biological_processes` binding. GO:0009612 response to mechanical
    stimulus was tried here and removed: it names a cell-level response, whereas
    this node is the tissue-scale mechanical insult itself -- the vessel
    indenting the root -- and not the nerve's response to it. The anatomy is
    carried by `locations`.
  evidence:
  - reference: PMID:25541189
    reference_title: Significance of neurovascular contact in classical trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurovascular contact was highly prevalent on the symptomatic compared to the asymptomatic side [53% versus 13%, P < 0.001, odds ratio = 11.6 (4.7-28.9), P < 0.001]. Severe neurovascular contact was caused by arteries in 98%."
    explanation: Blinded 3T MRI study establishing that it is severe contact, arterial in almost all cases, that associates with the painful side.
  - reference: PMID:25541189
    reference_title: Significance of neurovascular contact in classical trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurovascular contact is involved in the aetiology of classical trigeminal neuralgia and that it is caused by arteries located in the root entry zone"
    explanation: Localises the aetiologically relevant compression to the root entry zone specifically.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurovascular contact was found in 471 out of 531 symptomatic nerves (89%) and 244 of 681 asymptomatic nerves (36%), indicating high sensitivity but poor specificity."
    explanation: Meta-analytic figures showing why mere contact is insufficient, which is why this node is framed as morphological compression rather than contact.
  downstream:
  - target: Focal Demyelination and Axonal Juxtaposition
    causal_link_type: DIRECT
    description: >-
      Chronic compression at the root strips myelin over a short segment and
      brings bare axons into direct apposition without intervening glial
      processes.
    evidence:
    - reference: PMID:11701590
      reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Examination of trigeminal nerve roots from patients with compression of the nerve root by an overlying blood vessel has revealed focal demyelination in the region of compression, with close apposition of demyelinated axons and an absence of intervening glial processes."
      explanation: Direct histopathology of surgically obtained human nerve roots links the compression to the demyelinating lesion.
- name: Focal Demyelination and Axonal Juxtaposition
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The compressed segment of the root loses myelin and demyelinated axons come
    to lie against one another with no glial process between them. Because the
    proximal root is a central-nervous-system segment, the myelinating cell
    involved there is the oligodendrocyte rather than the Schwann cell. This is
    the lesion that the two aetiological routes of this disease converge on:
    vascular compression reaches it mechanically, multiple sclerosis reaches it
    immunologically, and a posterior fossa tumour reaches it by mass effect.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelin maintenance
    modifier: DECREASED
    term:
      id: GO:0043217
      label: myelin maintenance
  locations:
  - preferred_term: trigeminal nerve root
    term:
      id: UBERON:0004673
      label: trigeminal nerve root
  evidence:
  - reference: PMID:11701590
    reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is now persuasive evidence that trigeminal neuralgia is usually caused by demyelination of trigeminal sensory fibres within either the nerve root or, less commonly, the brainstem."
    explanation: States demyelination of the sensory fibres as the usual proximate cause, the claim this node represents.
  - reference: PMID:11701590
    reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases, the trigeminal nerve root demyelination involves the proximal, CNS part of the root and results from compression by an overlying artery or vein."
    explanation: Establishes that the demyelinated segment is the central (oligodendrocyte-myelinated) part of the root.
  downstream:
  - target: Ectopic Discharge and Ephaptic Cross-Excitation
    causal_link_type: DIRECT
    description: >-
      Bare, closely apposed axons permit spontaneous impulse generation and
      direct electrical spread from one fibre to its neighbours.
    evidence:
    - reference: PMID:11701590
      reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Experimental studies indicate that this anatomical arrangement favours the ectopic generation of spontaneous nerve impulses and their ephaptic conduction to adjacent fibres, and that spontaneous nerve activity is likely to be increased by the deformity associated with pulsatile vascular indentation."
      explanation: Ties the histological arrangement directly to ectopic generation and ephaptic conduction.
  - target: Dysregulated Voltage-Gated Sodium Channel Expression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - injury-induced transcriptional remodelling in trigeminal ganglion neurons
    description: >-
      Demyelinating injury of the root is followed by a change in which
      sodium-channel subunits the affected sensory neurons express and where
      those channels sit in the membrane.
    evidence:
    - reference: PMID:31908187
      reference_title: "Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Classic trigeminal neuralgia is associated with neurovascular compression in the trigeminal root entry zone, which can lead to demyelination and a dysregulation of voltage-gated sodium channel expression in the membrane."
      explanation: States the demyelination-to-channel-dysregulation step this edge represents.
- name: Dysregulated Voltage-Gated Sodium Channel Expression
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    Injured trigeminal sensory neurons remodel their voltage-gated sodium
    channel complement, lowering the threshold for impulse initiation and
    supporting repetitive high-frequency firing. This is the node that the
    first-line drugs act on: carbamazepine and oxcarbazepine stabilize the
    inactivated state of these channels. The specific subunit pattern is
    characterised mainly in rodent nerve-injury models rather than in human
    tissue, so the identity of the individual channels is held less firmly than
    the fact of the dysregulation.
  cell_types:
  - preferred_term: trigeminal ganglion sensory neuron
    term:
      id: CL:4023169
      label: trigeminal neuron
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    modifier: DYSREGULATED
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
  biological_processes:
  - preferred_term: regulation of membrane potential
    modifier: ABNORMAL
    term:
      id: GO:0042391
      label: regulation of membrane potential
  locations:
  - preferred_term: trigeminal ganglion
    term:
      id: UBERON:0001675
      label: trigeminal ganglion
  evidence:
  - reference: PMID:31908187
    reference_title: "Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classic trigeminal neuralgia is associated with neurovascular compression in the trigeminal root entry zone, which can lead to demyelination and a dysregulation of voltage-gated sodium channel expression in the membrane. These alterations may be responsible for pain attacks in trigeminal neuralgia patients."
    explanation: >-
      Quoted as a contiguous pair so the referent of the pronoun sits inside the
      quote rather than outside it -- the alterations named are the
      channel dysregulation this node represents.
  - reference: PMID:27327156
    reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "trigeminal ganglion in rats subjected to an infraorbital nerve-chronic constriction injury showed upregulation of Nav1.3 and downregulation of Nav1.7, Nav1.8, and Nav1.9 messenger RNA and protein levels"
    explanation: >-
      Rodent constriction-injury data give the direction of change for individual
      subunits. Marked INDIRECT because the model injures a peripheral trigeminal
      branch rather than reproducing root-entry-zone demyelination, and the
      subunit pattern has not been confirmed in human trigeminal ganglion.
  downstream:
  - target: Ectopic Discharge and Ephaptic Cross-Excitation
    causal_link_type: DIRECT
    description: >-
      A lowered firing threshold and altered channel kinetics make the injured
      afferents hyperexcitable, which is the precondition for the synchronized
      afterdischarge that generates a paroxysm.
    evidence:
    - reference: PMID:11803297
      reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Injury renders axons and axotomized somata hyperexcitable. The hyperexcitable afferents, in turn, give rise to pain paroxysms as a result of synchronized afterdischarge activity."
      explanation: States the hyperexcitability-to-synchronized-afterdischarge step that this edge asserts.
- name: Ectopic Discharge and Ephaptic Cross-Excitation
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    At the demyelinated segment, impulses arise where they should not and spread
    laterally between apposed bare axons. A light touch carried by large tactile
    afferents can therefore ignite activity in nociceptive fibres, and the
    resulting cross-excitation is amplified into a synchronized high-frequency
    burst. This is the step that explains the two features nothing else in the
    disease accounts for: that an innocuous stimulus in a small trigger zone
    provokes severe pain, and that the paroxysm builds, peaks, and stops
    abruptly with a refractory period afterwards.
  cell_types:
  - preferred_term: trigeminal ganglion sensory neuron
    term:
      id: CL:4023169
      label: trigeminal neuron
  biological_processes:
  - preferred_term: neuronal action potential
    modifier: INCREASED
    term:
      id: GO:0019228
      label: neuronal action potential
  - preferred_term: action potential propagation
    modifier: ABNORMAL
    term:
      id: GO:0098870
      label: action potential propagation
  evidence:
  - reference: PMID:11701590
    reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical observations and electrophysiological studies support the concept that demyelination and ephaptic spread of excitation underlie most, if not all, of these conditions."
    explanation: >-
      Explicitly generalises the demyelination-plus-ephaptic-spread mechanism
      across the vascular-compression cranial nerve hyperactivity syndromes,
      which is the basis for curating these subtypes on one pathograph.
  - reference: PMID:35860499
    reference_title: "The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, we can distinguish the following NVC conditions: trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. Also, rare cases of geniculate neuralgia and superior laryngeal neuralgia are reported."
    explanation: >-
      Independent corroboration of the lump/split decision from a 2022
      systematic review of 63 papers, two decades after Love and Coakham. It
      places trigeminal, glossopharyngeal, and geniculate (nervus intermedius)
      neuralgia on the same neurovascular-compression mechanism, which is the
      generalisation this entry's one-disease structure depends on.
  - reference: PMID:11803297
    reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The ignition hypothesis accounts for the major positive and negative signs and symptoms of trigeminal neuralgia, for its pathogenesis, and for the efficacy of treatment modalities."
    explanation: The ignition formulation is the mechanistic account this node encodes.
  - reference: PMID:11803297
    reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Proof, however, awaits the availability of key experimental data that can only be obtained from patients with trigeminal neuralgia."
    explanation: >-
      Recorded deliberately as a limit on the node: the authors state the
      mechanism is deduced rather than directly demonstrated in patients.
  downstream:
  - target: Paroxysmal Neuralgiform Pain
    causal_link_type: DIRECT
    description: >-
      The synchronized burst reaching central trigeminal pathways is experienced
      as a brief, abrupt, electric-shock-like paroxysm in the nerve's territory.
    evidence:
    - reference: PMID:11803297
      reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The hyperexcitable afferents, in turn, give rise to pain paroxysms as a result of synchronized afterdischarge activity."
      explanation: Directly states that synchronized afterdischarge produces the pain paroxysms.
- name: Paroxysmal Neuralgiform Pain
  role: outcome
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint of the graph: abrupt, severe, stabbing or
    electric-shock-like pain lasting seconds to two minutes, confined to the
    territory of the affected nerve, recurring in volleys and typically evoked
    by an innocuous trigger. Complete remissions lasting weeks to years are
    characteristic and distinguish it from most other neuropathic pain.
  biological_processes:
  - preferred_term: sensory perception of pain
    modifier: INCREASED
    term:
      id: GO:0019233
      label: sensory perception of pain
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical characterizations include notions of brief, sudden, stabbing, electric shock–like, and severe pain attacks."
    explanation: Describes the pain quality this outcome node represents.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike other forms of neuropathic pain, TN enters into periods of complete remission in up to 63% of patients."
    explanation: Supports the remitting-relapsing course stated in this node's description.
- name: Trigger Zone Mechanical Provocation
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Innocuous mechanical stimulation of a confined cutaneous or intraoral
    trigger zone — chewing, talking, shaving, a breath of cold air, or, for
    glossopharyngeal neuralgia, swallowing — sets off a paroxysm. Evoked attacks
    are so nearly universal in classical trigeminal neuralgia that their
    presence is a diagnostic criterion. Triggerability has been interpreted as a
    sign of cross-excitation between tactile and nociceptive fibres, which is
    the reading this graph follows, but it is an interpretation rather than a
    directly demonstrated coupling.
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in sensory perception
    term:
      id: GO:0050974
      label: detection of mechanical stimulus involved in sensory perception
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the few studies that examined trigger stimuli or maneuvers in classical TN, evoked pain was reported in 99% of the patients."
    explanation: Quantifies how nearly universal trigger-evoked pain is, supporting this as a mechanism node rather than an incidental feature.
  downstream:
  - target: Ectopic Discharge and Ephaptic Cross-Excitation
    causal_link_type: DIRECT
    description: >-
      Afferent traffic from the trigger zone enters the demyelinated segment and
      ignites cross-excitation into nociceptive fibres.
    evidence:
    - reference: PMID:11701590
      reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Experimental studies indicate that this anatomical arrangement favours the ectopic generation of spontaneous nerve impulses and their ephaptic conduction to adjacent fibres"
      explanation: >-
        Supports ephaptic conduction to adjacent fibres as the substrate for
        trigger-evoked attacks. Marked INDIRECT because this sentence concerns
        spontaneous impulses; it does not itself demonstrate that trigger-zone
        afferent traffic is the igniting input.
- name: Central Demyelinating Plaque in Multiple Sclerosis
  role: trigger
  biological_scale: TISSUE
  description: >-
    In secondary disease due to multiple sclerosis, an inflammatory
    demyelinating plaque involving the pontine trigeminal pathways or the root
    entry zone produces the same demyelinated, bare-axon segment that vascular
    compression produces mechanically. Increased susceptibility of the root to
    coexisting neurovascular contact has also been proposed. Bilateral disease,
    which is otherwise almost unknown, should raise suspicion of this route.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  evidence:
  - reference: PMID:11701590
    reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar foci of nerve root demyelination and juxtaposition of axons have been demonstrated in multiple sclerosis patients with trigeminal neuralgia."
    explanation: Human pathology showing that the MS route converges on the same histological lesion.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The development of pain paroxysms has variably been explained with the presence of demyelinating plaques in the pons or increased susceptibility of the trigeminal nerve root to neurovascular compression."
    explanation: Records that both explanations for MS-associated disease remain on the table, which is why this node is not asserted as a single settled route.
  downstream:
  - target: Focal Demyelination and Axonal Juxtaposition
    causal_link_type: DIRECT
    description: >-
      The plaque is itself the demyelinating lesion, so this route enters the
      shared graph at the demyelination node rather than upstream of it.
    evidence:
    - reference: PMID:11701590
      reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other causes of trigeminal neuralgia in which demyelination is involved or implicated include multiple sclerosis and, probably, compressive space-occupying masses in the posterior fossa."
      explanation: Names multiple sclerosis as a demyelination-mediated cause, placing this node upstream of the shared demyelination node.
- name: Posterior Fossa Mass Compressing the Nerve Root
  role: trigger
  biological_scale: TISSUE
  description: >-
    A cerebellopontine-angle tumour, most often benign, compresses the root near
    its entry into the pons and induces focal demyelination in the same way an
    artery does. Malignant tumours behave differently: they tend to infiltrate
    the nerve and cause axonal degeneration, which produces a sensory deficit
    and a pain phenotype that does not resemble neuralgia. Tumour and multiple
    sclerosis together account for roughly 15% of trigeminal neuralgia, which is
    why imaging is required rather than optional.
  locations:
  - preferred_term: trigeminal nerve root
    term:
      id: UBERON:0004673
      label: trigeminal nerve root
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumors leading to TN are mostly benign and typically compress the root near its entry into the pons. The compression induces focal demyelination and is thought to trigger paroxysmal ectopic discharges."
    explanation: States the tumour-compression-to-demyelination-to-ectopic-discharge route this node represents.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A tumor at the cerebellopontine angle or MS causes TN in 15% of patients."
    explanation: Quantifies the combined secondary-aetiology fraction cited in this node's description.
  downstream:
  - target: Focal Demyelination and Axonal Juxtaposition
    causal_link_type: DIRECT
    description: >-
      Mass effect at the root entry zone produces the same focal demyelinating
      lesion as arterial compression.
    evidence:
    - reference: PMID:27306631
      reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The compression induces focal demyelination and is thought to trigger paroxysmal ectopic discharges."
      explanation: Directly asserts the compression-to-demyelination link for the tumour route.
- name: Extracranial Entrapment of the Occipital Nerves
  role: trigger
  biological_scale: TISSUE
  description: >-
    The mechanism proposed for occipital neuralgia, and the reason that subtype
    sits apart from the rest of this entry. The greater, lesser, and third
    occipital nerves are compressed at defined points along their extracranial
    course — where the greater occipital nerve curves around the obliquus capitis
    inferior, pierces the semispinalis capitis and trapezius, and crosses the
    occipital artery. There is no brainstem root entry zone involved, and this
    node is deliberately not connected to the demyelination-and-ephaptic chain,
    because the evidence for that chain comes from cranial nerve roots and has
    not been shown for these nerves.
  evidence:
  - reference: PMID:39217283
    reference_title: "An anatomical analysis of the occipital nerve complex: an essential tool for the application of occipital nerve blocks."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Six, four, and one potential entrapment points were detected for the GON, TON, and LON, respectively."
    explanation: >-
      Cadaveric dissection study establishing that the compression points
      relevant to these nerves are extracranial sites along their course rather
      than a root entry zone. Marked INDIRECT because it maps anatomy and does
      not show that entrapment at those points causes occipital neuralgia, and
      OTHER because it is a dissection study with no patients or cohort.
  downstream:
  - target: Paroxysmal Neuralgiform Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Entrapment of the occipital nerves is followed by lancinating pain in
      their territory. The intervening steps are not established for these
      nerves, and are deliberately not assumed to be the ephaptic mechanism
      demonstrated for cranial nerve roots.
    evidence:
    - reference: PMID:24737457
      reference_title: Occipital neuralgia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Occipital neuralgia is an uncommon cause of occipital pain characterized by paroxysmal lancinating pain in the distribution of the greater, lesser or third occipital nerves."
      explanation: >-
        Establishes the pain endpoint in the occipital nerve territory. Graded
        INDIRECT because it describes the phenotype and does not itself
        demonstrate the entrapment-to-pain causal step.
phenotypes:
- category: Neurological
  name: Paroxysmal Lancinating Facial Pain
  description: >-
    Brief, abrupt, severe electric-shock-like pain attacks confined to the
    trigeminal territory, lasting seconds to two minutes and recurring from once
    to over fifty times a day.
  frequency: OBLIGATE
  subtype: Trigeminal
  phenotype_term:
    preferred_term: Trigeminal neuralgia
    term:
      id: HP:0100661
      label: Trigeminal neuralgia
    temporality: RECURRENT
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The paroxysms may last up to 2 minutes, but their duration is usually limited to a few seconds. Frequency of the pain attacks may range from 1 to over 50 a day."
    explanation: Quantifies attack duration and frequency for this phenotype.
- category: Neurological
  name: Unilateral Pain Distribution
  description: >-
    Pain is virtually always confined to one side. Truly simultaneous bilateral
    pain is essentially unreported in classical disease and, where bilateral
    involvement occurs over the course of illness, points towards multiple
    sclerosis.
  frequency: VERY_FREQUENT
  subtype: Trigeminal
  phenotype_term:
    preferred_term: Strictly unilateral pain distribution
  notes: >-
    Left unbound on purpose. This record is a laterality claim, and HPO has no
    term for it; the schema's `LateralityEnum` has no UNILATERAL value either.
    Binding HP:0033345 Neuralgia here would restate the pain concept already
    bound on the first phenotype without expressing the laterality, so the
    free-text `preferred_term` is kept instead.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Painful symptoms associated with TN are virtually always unilateral. Bilateral TN is very rare except for TN caused by multiple sclerosis (MS)."
    explanation: Supports both the unilaterality and its exception in multiple sclerosis.
- category: Neurological
  name: Concomitant Persistent Background Pain
  description: >-
    Roughly half of patients have continuous aching or burning pain in the same
    territory in addition to the paroxysms. It occurs across all three
    aetiological categories, and evidence that it improves independently of the
    paroxysms after decompression suggests the two components have distinct
    mechanisms.
  frequency: FREQUENT
  subtype: Trigeminal
  phenotype_term:
    preferred_term: Chronic pain
    term:
      id: HP:0012532
      label: Chronic pain
    temporality: CHRONIC
  evidence:
  - reference: PMID:25231219
    reference_title: Trigeminal neuralgia--a prospective systematic study of clinical characteristics in 158 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, 78 (49%) had concomitant persistent pain in addition to paroxysmal stabbing pain."
    explanation: Prospective series quantifying the fraction with a persistent pain component.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is, however, compelling evidence that continuous and paroxysmal pain may improve independently after microvascular decompression, suggesting that the mechanisms responsible for the 2 pain components are distinct"
    explanation: Supports the claim that the persistent component is mechanistically separate from the paroxysms.
- category: Neurological
  name: Trigger-Evoked Attacks
  description: >-
    Attacks provoked by innocuous mechanical stimulation of a confined trigger
    zone — light touch, chewing, talking, shaving, cold air. Purely spontaneous
    disease is essentially unknown, and triggerability is used as a positive
    diagnostic criterion.
  frequency: VERY_FREQUENT
  subtype: Trigeminal
  phenotype_term:
    preferred_term: Trigger-zone-evoked pain paroxysm
  notes: >-
    Deliberately left unbound. HP:0012533 Allodynia is the obvious candidate and
    is wrong: the source cited here separates the two explicitly, noting that
    confined trigger zones and the refractory period after an attack distinguish
    triggered neuralgia from mechanical allodynia. No HPO term expresses
    trigger-zone-evoked paroxysm, so a free-text `preferred_term` is kept rather
    than asserting allodynia.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore we propose that triggered pain qualifies as criterion supporting the diagnosis of clinically established TN"
    explanation: Supports triggerability as a defining, diagnostically used feature.
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Confined trigger zones and a common combination with brisk muscle contractions (tics) help distinguish triggered TN from allodynia in other conditions of neuropathic pain."
    explanation: The source separating triggered neuralgia from allodynia, which is why no HPO term is bound here.
- category: Neurological
  name: Sensory Deficit in the Affected Territory
  description: >-
    Clinically detectable loss of sensation is uncommon in classical disease but
    is found in about a third of patients with disease secondary to a tumour or
    multiple sclerosis, so its presence should prompt investigation. Subtle
    abnormalities are common on quantitative sensory testing even in classical
    disease, and their absence does not rule out a secondary cause.
  frequency: OCCASIONAL
  subtype: Trigeminal
  diagnostic: true
  phenotype_term:
    preferred_term: Hypoesthesia
    term:
      id: HP:0033748
      label: Hypoesthesia
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical deficits of discriminatory sensory functions are highly suspicious of TN caused by a major underlying disease. They occurred in 25 out of 67 patients (37%) with TN secondary to tumors or MS."
    explanation: >-
      Quoted as a contiguous pair so the referent of the pronoun sits inside the
      quote. Quantifies sensory deficit frequency in secondary disease, which is
      what makes it diagnostically useful.
  - reference: PMID:25231219
    reference_title: Trigeminal neuralgia--a prospective systematic study of clinical characteristics in 158 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients who had not undergone surgery for TN had sensory abnormalities in 35 (29%)."
    explanation: Shows sensory abnormalities are not confined to secondary disease or to post-surgical patients.
- category: Neurological
  name: Cranial Autonomic Features
  description: >-
    Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea, or
    flushing accompanying the pain. Their presence does not by itself reclassify
    the condition as a trigeminal autonomic cephalalgia, which is a common
    diagnostic trap.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ictal lacrimation
    term:
      id: HP:0031731
      label: Increased tear production
  evidence:
  - reference: DOI:10.22514/jofph.2024.023
    reference_title: "Autonomic features of craniofacial neuralgias: a systematic review with meta-analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "40% of all patients with craniofacial neuralgias had at least one autonomic feature."
    explanation: Meta-analytic estimate of how often autonomic features accompany craniofacial neuralgia.
  - reference: DOI:10.22514/jofph.2024.023
    reference_title: "Autonomic features of craniofacial neuralgias: a systematic review with meta-analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With trigeminal neuralgia, the most common autonomic feature was lacrimation, and the least common was nasal congestion."
    explanation: Identifies lacrimation as the commonest autonomic accompaniment in trigeminal neuralgia, which is the phenotype term bound here.
  - reference: PMID:25231219
    reference_title: Trigeminal neuralgia--a prospective systematic study of clinical characteristics in 158 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic symptoms were present in 48 (31%)."
    explanation: Independent prospective series giving a concordant frequency.
- category: Neurological
  name: Deep Ear Pain
  description: >-
    Paroxysmal pain felt deep in the ear, radiating to the auditory canal,
    auricle, mastoid, soft palate, temple, or angle of the jaw. Characteristic of
    nervus intermedius neuralgia, and a major source of diagnostic overlap with
    glossopharyngeal neuralgia.
  subtype: Nervus Intermedius
  phenotype_term:
    preferred_term: Ear pain
    term:
      id: HP:0030766
      label: Ear pain
  evidence:
  - reference: PMID:39847207
    reference_title: Nervus Intermedius Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NIN presents as a rare neuralgia of this nerve, causing deep ear pain, which may radiate to the auditory canal, auricle, mastoid, soft palate, temple, and angle of the jaw."
    explanation: Defines the pain territory of this phenotype.
- category: Neurological
  name: Occipital Scalp Pain
  description: >-
    Paroxysmal lancinating pain over the posterior scalp in the greater, lesser,
    or third occipital nerve distribution, frequently mistaken for cervicogenic
    headache or migraine.
  subtype: Occipital
  phenotype_term:
    preferred_term: Occipital neuralgia
    term:
      id: HP:0012318
      label: Occipital neuralgia
  evidence:
  - reference: PMID:24737457
    reference_title: Occipital neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occipital pain is a common complaint amongst patients with headache, and the differential can include many primary headache disorders such as cervicogenic headache or migraine."
    explanation: Supports both the location of the pain and the differential-diagnostic difficulty noted in the description.
- category: Cardiovascular
  name: Reflex Bradycardia and Cardiac Syncope During Attacks
  description: >-
    A rare but dangerous complication specific to the glossopharyngeal subtype.
    Because the glossopharyngeal nerve carries the carotid-sinus afferent limb,
    a pain paroxysm can recruit the vagal efferent arc and produce bradycardia,
    hypotension, sinus pauses, and syncope. Recognising it matters out of
    proportion to its frequency, because it changes management from pain control
    alone to cardiac monitoring and possible pacing.
  frequency: VERY_RARE
  subtype: Glossopharyngeal
  phenotype_term:
    preferred_term: Syncope during a neuralgic paroxysm
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:27102416
    reference_title: Glossopharyngeal neuralgia associated with cardiac syncope.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even more uncommon is the association between glossopharyngeal neuralgia and cardiac syncope. In these patients, the cardiovascular consequences may include bradycardia, hypotension and cardiac arrest."
    explanation: >-
      Supports the association and names the cardiovascular consequences. This
      is a single case report, so it establishes that the phenomenon occurs
      rather than how often, which is why the frequency is recorded as VERY_RARE.
  - reference: PMID:27102416
    reference_title: Glossopharyngeal neuralgia associated with cardiac syncope.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple pauses including one lasting 14 s were noted on ambulatory ECG monitoring."
    explanation: Objective conduction pauses on monitoring, which is what makes this a cardiac rather than a purely painful complication.
diagnosis:
- name: MRI of the posterior fossa and cranial nerves
  description: >-
    High-resolution MRI is required rather than optional, because no clinical
    feature reliably excludes a secondary cause. It serves two purposes at once:
    excluding tumour, multiple sclerosis, aneurysm, and vascular malformation,
    and grading the degree of neurovascular contact to inform whether and when
    to refer for decompression. Demonstrating contact does not confirm the
    diagnosis.
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN."
    explanation: Guideline recommendation establishing MRI as a required part of the work-up and the reason for it.
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression."
    explanation: Supports the stated limit on how imaging findings should be used.
- name: Trigeminal reflex recording
  description: >-
    Electrophysiological alternative when MRI cannot be performed. Reflex
    abnormalities discriminate secondary from primary disease with accuracy
    comparable to MRI.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reflex abnormalities achieve a sensitivity of 94% and specificity of 87% to identify secondary TN, comparable to the diagnostic accuracy of MRI."
    explanation: Gives the diagnostic performance figures that justify this as an MRI substitute.
treatments:
- name: Carbamazepine
  description: >-
    First-line pharmacotherapy. Stabilizes voltage-gated sodium channels in
    their inactivated state, which raises the threshold for the repetitive
    high-frequency firing that generates a paroxysm. Sedation, dizziness,
    ataxia, hyponatraemia, hepatic and haematologic toxicity, rash, and drug
    interactions require monitoring.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_mechanisms:
  - target: Dysregulated Voltage-Gated Sodium Channel Expression
    treatment_effect: INHIBITS
    description: >-
      Sodium-channel blockade acts directly on the remodelled channels that
      underlie the lowered firing threshold, suppressing high-frequency
      discharge before it can synchronize into a paroxysm.
    evidence:
    - reference: PMID:31908187
      reference_title: "Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Their mechanism of action is a modulation of voltage-gated sodium channels, leading to a decrease in neuronal activity."
      explanation: States the sodium-channel mechanism that connects this drug to the channel-dysregulation node.
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice."
    explanation: Guideline recommendation establishing first-line status.
- name: Oxcarbazepine
  description: >-
    First-line alternative to carbamazepine with the same sodium-channel
    mechanism and a generally more favourable interaction and tolerability
    profile, though hyponatraemia remains a concern.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
  target_mechanisms:
  - target: Dysregulated Voltage-Gated Sodium Channel Expression
    treatment_effect: INHIBITS
    description: >-
      Shares the sodium-channel-modulating mechanism of carbamazepine and acts
      on the same node.
    evidence:
    - reference: PMID:31908187
      reference_title: "Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The antiepileptic drugs carbamazepine and oxcarbazepine are the first-line pharmacological treatment for trigeminal neuralgia. Their mechanism of action is a modulation of voltage-gated sodium channels, leading to a decrease in neuronal activity."
      explanation: Names oxcarbazepine and states its sodium-channel mechanism in the same quoted passage, so the mechanism claim stands on the quote itself.
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice."
    explanation: Guideline recommendation establishing first-line status alongside carbamazepine.
- name: Second-Line and Add-On Anticonvulsant Therapy
  description: >-
    Lamotrigine, gabapentin, pregabalin, baclofen, and phenytoin are used alone
    or added to a first-line agent when it fails or is not tolerated. For
    glossopharyngeal neuralgia the same first-line-then-alternatives approach is
    applied, with gabapentin and eslicarbazepine acetate as the usual
    alternatives.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
    - preferred_term: pregabalin
      term:
        id: CHEBI:64356
        label: pregabalin
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy."
    explanation: Guideline listing of the second-line and add-on agents named here.
  - reference: DOI:10.52965/001c.36042
    reference_title: "Glossopharyngeal Neuralgia: Epidemiology, Risk factors,   Pathophysiology, Differential diagnosis, and Treatment Options  "
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conservatively, first-line management of GPN is carbamazepine, but gabapentin and eslicarbazepine acetate are suitable alternatives."
    explanation: Supports the same drug strategy applying to the glossopharyngeal subtype.
- name: Intravenous Therapy for Acute Exacerbation
  description: >-
    Intravenous fosphenytoin or lidocaine for a crisis of uncontrolled attacks,
    where oral titration is too slow and the patient may be unable to eat or
    drink.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fosphenytoin
      term:
        id: CHEBI:5165
        label: Fosphenytoin
    - preferred_term: lidocaine
      term:
        id: CHEBI:6456
        label: lidocaine
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used."
    explanation: Guideline recommendation for the acute crisis setting.
- name: Microvascular Decompression
  description: >-
    Posterior fossa craniotomy to interpose material between the offending
    vessel and the nerve root, leaving the nerve intact. It is the only
    cause-directed treatment and gives the most durable medication-free relief,
    but carries the risks of a posterior fossa operation. Recommended as
    first-line surgery in classical disease; where MRI shows no neurovascular
    contact, ablative procedures are preferred instead.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Neurosurgical Procedure
    term:
      id: NCIT:C15656
      label: Neurosurgical Procedure
  target_mechanisms:
  - target: Neurovascular Compression at the Nerve Root Entry Zone
    treatment_effect: INHIBITS
    description: >-
      Separating the vessel from the root removes the compressive lesion itself.
      The rapidity of relief argues that the immediate benefit comes from ending
      the focal distortion and separating the apposed demyelinated axons rather
      than from remyelination, which may instead be what sustains relief and
      what underlies spontaneous remission.
    evidence:
    - reference: PMID:11701590
      reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Decompression of the nerve root produces rapid relief of symptoms in most patients with vessel-associated trigeminal neuralgia, probably because the resulting separation of demyelinated axons and their release from focal distortion reduce the spontaneous generation of impulses and prevent their ephaptic spread."
      explanation: >-
        Directly links the operation to reversal of the compression node and, through
        it, to suppression of ectopic generation and ephaptic spread.
  evidence:
  - reference: PMID:8598865
    reference_title: The long-term outcome of microvascular decompression for trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten years after surgery, 70 percent of the patients (as determined by Kaplan-Meier analysis) had excellent final results-that is, they were free of pain without medication for tic."
    explanation: Long-term prospective follow-up of 1185 patients quantifying durable medication-free relief.
  - reference: PMID:8598865
    reference_title: The long-term outcome of microvascular decompression for trigeminal neuralgia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major complications included two deaths shortly after the operation (0.2 percent) and one brain-stem infarction (0.1 percent). Sixteen patients (1 percent) had ipsilateral hearing loss."
    explanation: Records the operative risk that qualifies the benefit claim.
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microvascular decompression is recommended as first-line surgery in patients with classical TN."
    explanation: Guideline recommendation establishing the place of this operation.
  - reference: PMID:28263933
    reference_title: "Microvascular Decompression for Glossopharyngeal Neuralgia: Long-Term Follow-Up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 33 patients (94.3%) experienced complete pain relief immediately after MVD."
    explanation: Shows the same cause-directed operation works for the glossopharyngeal subtype.
- name: Percutaneous Ablative Procedures
  description: >-
    Radiofrequency thermocoagulation, balloon compression, or glycerol
    rhizolysis of the trigeminal ganglion. Preferred where imaging shows no
    neurovascular contact, and in older or higher-risk patients who would not
    tolerate a craniotomy. They trade pain control for sensory loss:
    facial numbness, dysaesthesia, corneal anaesthesia, masseter weakness, and
    rarely anaesthesia dolorosa. Note that the bound `treatment_term` names
    radiofrequency ablation specifically; NCIT has no clinical-action term
    covering the balloon-compression and glycerol-rhizolysis alternatives
    grouped here, so the binding is narrower than this entry.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Radiofrequency Ablation
    term:
      id: NCIT:C15666
      label: Radiofrequency Ablation
  target_mechanisms:
  - target: Ectopic Discharge and Ephaptic Cross-Excitation
    treatment_effect: INHIBITS
    description: >-
      Unlike decompression, these procedures do not remove the cause; they
      lesion the conducting pathway so that ectopic and ephaptically spread
      activity cannot reach central pathways. The sensory deficit they produce
      is the direct cost of that non-selective approach.
    evidence:
    - reference: PMID:30860637
      reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact."
      explanation: >-
        Supports the indication for these procedures. Marked INDIRECT because the
        guideline states when to use them, not the conduction-block mechanism
        asserted in this link's description.
  evidence:
  - reference: DOI:10.1186/s12883-023-03415-z
    reference_title: "Percutaneous radiofrequency thermocoagulation and microvascular decompression for treating glossopharyngeal neuralgia: a retrospective clinical study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 48 weeks, the complete remission rate was significantly higher (P < 0.05) in the MVD group than in PRT group. No significant difference in adverse reactions was observed between the two groups."
    explanation: >-
      Head-to-head comparison in the glossopharyngeal subtype showing that the
      cause-directed operation buys more complete remission than ablation, which
      is the trade-off this entry models as decompression acting on the
      compression node and ablation acting only on the discharge node.
  - reference: DOI:10.1186/s12883-023-03415-z
    reference_title: "Percutaneous radiofrequency thermocoagulation and microvascular decompression for treating glossopharyngeal neuralgia: a retrospective clinical study"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The length of hospital stay, operative time, and cost were significantly higher (P < 0.05) in the MVD group than in the PRT group."
    explanation: >-
      The countervailing cost of the more definitive operation, which is why
      ablation remains the option for higher-risk patients. The quoted sentence
      states those costs directly. Note the design is a retrospective
      single-centre comparison, so the size of the difference should not be
      read as a general estimate.
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN."
    explanation: Records the guideline's explicit equipoise between ablative options in idiopathic disease.
- name: Stereotactic Radiosurgery
  description: >-
    Focused radiation to the trigeminal root, avoiding open surgery at the cost
    of delayed onset of relief and a meaningful recurrence rate. Suitable where
    craniotomy is not appropriate.
  action_category: THERAPEUTIC
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiosurgery
    term:
      id: NCIT:C15696
      label: Radiosurgery
  evidence:
  - reference: PMID:37144649
    reference_title: Long-Term Efficacy of Gamma Knife Radiosurgery on Pain Control in Trigeminal Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial pain relief rate was 85%, with a median period of 25 (range, 1-90) days. At the final follow-up, 62.5% of patients had adequate pain relief."
    explanation: >-
      163-patient series quantifying both the delayed onset of relief and its
      attrition over follow-up, which are the two properties this treatment's
      description turns on.
  - reference: PMID:37144649
    reference_title: Long-Term Efficacy of Gamma Knife Radiosurgery on Pain Control in Trigeminal Neuralgia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predicted adequate pain relief rates at the 3rd and 6th month and 1st, 3rd, 5th, and 7th year were 84%, 79%, 76%, 67%, 59%, and 55%, respectively."
    explanation: >-
      The declining curve behind the recurrence-risk claim. Marked INDIRECT
      because these are model-predicted rather than directly observed rates.
  - reference: PMID:38385643
    reference_title: Long-term outcomes of Gamma Knife radiosurgery in treating glossopharyngeal neuralgia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gamma Knife radiosurgery is a non-invasive, efficacious treatment option for idiopathic GPN, offering short- and long-term relief without permanent complications."
    explanation: >-
      Extends the option to the glossopharyngeal subtype, which the quoted
      conclusion asserts directly. It rests on eight patients, so it establishes
      that the option is used and reported rather than a general efficacy rate.
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is recommended that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated."
    explanation: >-
      The general indication for procedural treatment. Marked INDIRECT because
      the guideline abstract does not name radiosurgery specifically.
- name: Botulinum Toxin Type A Injection
  description: >-
    Off-label option for refractory disease, injected into the painful
    territory. Listed by guideline among the agents that may be used alone or as
    add-on therapy; meta-analysis of randomized trials supports a treatment
    effect.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Botulinum Toxin Therapy
    term:
      id: NCIT:C157775
      label: Botulinum Toxin Therapy
    therapeutic_agent:
    - preferred_term: onabotulinumtoxinA
      term:
        id: CHEBI:3160
        label: Botulinum toxin type A
  evidence:
  - reference: PMID:27377706
    reference_title: "Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite limited data, our results suggest that BTX-A may be an effective and safe treatment option for patients with TN."
    explanation: >-
      Meta-analysis of four randomized trials concluding a probable treatment
      effect. The authors' own hedge on the limited data is kept in the quote
      rather than trimmed away.
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy."
    explanation: Guideline placement of botulinum toxin among add-on options.
- name: Occipital Nerve Block
  description: >-
    Local anaesthetic with or without corticosteroid injected at the greater
    occipital nerve. First-line minimally invasive intervention for occipital
    neuralgia and used diagnostically, though relief is often short-lived and
    blocks also relieve migraine, so a response is not specific.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Occipital Nerve Block
    term:
      id: NCIT:C157940
      label: Occipital Nerve Block
  target_mechanisms:
  - target: Extracranial Entrapment of the Occipital Nerves
    treatment_effect: INHIBITS
    description: >-
      The block is delivered at the anatomical entrapment points along the
      nerve's extracranial course, which is why the procedure targets this node
      rather than the root-entry-zone node.
    evidence:
    - reference: PMID:39217283
      reference_title: "An anatomical analysis of the occipital nerve complex: an essential tool for the application of occipital nerve blocks."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "we aimed to investigate the potential compression points of the greater occipital nerve (GON), third occipital nerve (TON), and lesser occipital nerve (LON) which are targeted to block in occipital nerve blocks"
      explanation: >-
        Establishes that the compression points are the anatomical targets of the
        block. Marked INDIRECT because it is a cadaveric dissection study and
        reports no clinical outcomes.
  evidence:
  - reference: PMID:34287719
    reference_title: Occipital Neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The occipital nerve block is considered the first line in a minimally invasive intervention, but the duration of relief may be short term."
    explanation: Supports both the first-line placement and the durability caveat.
  - reference: PMID:24737457
    reference_title: Occipital neuralgia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, nerve blocks are also effective in migraine headache and misdiagnosis can result in a false positive."
    explanation: Records the limit on using a block response as a diagnostic test.
- name: Psychological and Nursing Support
  description: >-
    Guideline-recommended alongside medical and surgical management. The
    recurrent excruciating pain, impaired eating and speech, and medication
    burden carry a substantial psychiatric and functional cost that drug and
    procedural treatment do not address on their own.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30860637
    reference_title: European Academy of Neurology guideline on trigeminal neuralgia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support."
    explanation: Direct guideline recommendation for this component of care.
genetic:
- name: C8B
  gene_term:
    preferred_term: C8B
    term:
      id: hgnc:1353
      label: C8B
  relationship_type: SUSCEPTIBILITY
  association: Candidate-gene susceptibility association; not causative
  subtype: Trigeminal
  notes: >-
    Included as a susceptibility signal, not a disease gene. Three caveats
    travel with it and should not be dropped if this record is reused. First,
    this is a targeted candidate-gene analysis of 175 SNPs in 17 genes chosen
    from the same group's earlier proteomic work, not a genome-wide scan, so
    p = 0.00016 is nowhere near the 5e-8 threshold a GWAS hit would need and the
    result is not corrected for genome-wide multiple testing. Second, the effect
    is small (OR 1.357) -- population-level risk modification, not anything that
    would explain an individual case. Third, it is a single cohort and has not
    been replicated. Nothing here displaces neurovascular compression as the
    mechanism; C8B is a complement component and the proposed link is to
    neuroinflammation, which this entry's pathograph does not currently model.
  evidence:
  - reference: DOI:10.1007/s12031-024-02263-x
    reference_title: Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two SNPs corresponding to C8B rs706484 [odds ratio (OR) (95% confidence interval (CI)): 1.357 (1.158–1.590); p: 0.00016] and MFG-E8 rs2015495 [OR (95% CI): 1.313 (1.134–1.521); p: 0.00028] showed significant positive association with TN"
    explanation: >-
      UK Biobank case-control association giving the effect size for this gene.
      The quoted sentence states the association itself, which is exactly what
      the SUSCEPTIBILITY relationship_type claims -- an association in one
      cohort, not a causal role.
  - reference: DOI:10.1007/s12031-024-02263-x
    reference_title: Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identified genetic variations may help explain why some individuals develop TN while others do not, indicating a potential genetic predisposition to the condition."
    explanation: >-
      The authors' own framing, which is predisposition rather than causation --
      the reason `relationship_type` here is SUSCEPTIBILITY.
- name: MFGE8
  gene_term:
    preferred_term: MFGE8
    term:
      id: hgnc:7036
      label: MFGE8
  relationship_type: SUSCEPTIBILITY
  association: Candidate-gene susceptibility association; not causative
  subtype: Trigeminal
  notes: >-
    Same study, same caveats as the C8B record above: candidate-gene design, no
    genome-wide correction, OR 1.313, single unreplicated cohort. MFG-E8 is
    proposed to act through regulation of neuroinflammation.
  evidence:
  - reference: DOI:10.1007/s12031-024-02263-x
    reference_title: Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest novel genetic associations between C8B, a key component of the complement system, and MFG-E8, which plays a role in regulating neuroinflammation, in relation to TN."
    explanation: >-
      Names both genes and the proposed biology in the quoted sentence itself.
      The authors state a suggestion of association rather than an established
      mechanism, which is why this entry records susceptibility and does not
      wire either gene into the pathograph.
  - reference: DOI:10.1007/s12031-024-02263-x
    reference_title: Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study sample comprised of diagnosed TN cases (N = 555) and randomly matched controls (N = 6245) based on specific criteria."
    explanation: The cohort size behind the association, recorded so the strength of the claim can be judged from the entry.
environmental:
- name: Chronic arterial hypertension
  description: >-
    Hypertension is associated with an increased subsequent risk of trigeminal
    neuralgia in population data. The proposed link is through arterial
    elongation, tortuosity, and stiffening, which make a compressive vascular
    loop at the root entry zone more likely — an association, not a demonstrated
    causal pathway.
  effect: Increases risk of subsequent trigeminal neuralgia
  notes: >-
    Deliberately left without an `exposure_term`. ECTO was searched and carries
    only exposure-to-antihypertensive-agent concepts (ECTO:2000001,
    ECTO:9001744), which describe treatment rather than the hypertensive state
    itself; XCO likewise offers only `antihypertensive agent`. Binding either
    would assert the opposite of the claim made here. Note also that
    hypertension is a host physiological state rather than an external
    exposure, and is placed in `environmental:` because that is where this
    schema carries modifiable, non-genetic risk factors.
  influences_mechanisms:
  - target: Neurovascular Compression at the Nerve Root Entry Zone
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypertensive vascular remodelling is the proposed route by which
      hypertension raises the probability of a compressive arterial loop
      contacting the nerve root. The intervening steps have not been
      demonstrated.
    evidence:
    - reference: PMID:21998318
      reference_title: "Increased risk of trigeminal neuralgia after hypertension: a population-based study."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study shows a significantly increased risk of developing TN after hypertension. Further studies are needed to elucidate the underlying mechanism of the association between hypertension and TN."
      explanation: >-
        Population cohort of 138,492 hypertensive persons establishing the
        temporal association. Marked INDIRECT because the authors state
        explicitly that the underlying mechanism is not established, so this
        supports the risk relationship but not the vascular-remodelling route
        this link proposes.
  evidence:
  - reference: PMID:2301931
    reference_title: "Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945-1984."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study indicates an elevated relative risk associated with hypertension (both overall and among women in the cohort)."
    explanation: Independent population-based cohort reporting the same association.
animal_models:
- name: Rat infraorbital nerve chronic constriction injury
  species: Rat
  genotype: Wild-type Sprague-Dawley
  publication: PMID:27327156
  description: >-
    A ligature is placed around the infraorbital branch of the trigeminal nerve,
    producing a sustained drop in facial mechanical threshold and a measurable
    change in trigeminal ganglion sodium-channel expression. It is the source of
    the subunit-level detail in this entry's channel node, and it is included
    here explicitly so that the model's limits are attached to the graph rather
    than left in prose.
  evidence:
  - reference: PMID:27327156
    reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We used the infraorbital nerve-chronic constriction injury model of TN in the rat."
    explanation: Establishes the model preparation this entry describes.
  modeled_mechanisms:
  - target: Dysregulated Voltage-Gated Sodium Channel Expression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The model does reproduce injury-driven remodelling of voltage-gated sodium
      channel expression in trigeminal ganglion neurons, which is the claim this
      node makes.
    limitations: >-
      It injures a distal peripheral branch, whereas the human lesion is focal
      demyelination of the central, oligodendrocyte-myelinated segment of the
      root -- a different site and a different myelinating cell. The subunit
      pattern it reports has not been confirmed in human trigeminal ganglion.
    readouts:
    - name: Nav1.3 transcript and protein in trigeminal ganglion
      target: Dysregulated Voltage-Gated Sodium Channel Expression
      direction: INCREASED
      interpretation: Upregulation of a channel subunit associated with neuronal hyperexcitability after injury.
      evidence:
      - reference: PMID:27327156
        reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "trigeminal ganglion in rats subjected to an infraorbital nerve-chronic constriction injury showed upregulation of Nav1.3 and downregulation of Nav1.7, Nav1.8, and Nav1.9 messenger RNA and protein levels"
        explanation: Reports the measured direction of change for each subunit, including the Nav1.3 increase this readout records.
    evidence:
    - reference: PMID:27327156
      reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings suggest that VGSC may participate in the regulation of TN."
      explanation: >-
        The authors' own claim for the model is a suggestion that these channels
        participate, which is the strength this link is graded at.
  - target: Paroxysmal Neuralgiform Pain
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model does not reproduce the defining clinical phenotype. Human
      cranial neuralgia is brief, trigger-evoked, and remitting; the model
      produces a sustained lowering of mechanical threshold over weeks.
    limitations: >-
      There is no trigger zone, no paroxysm, no refractory period, and no
      remission in this preparation, so it cannot be used to test claims about
      the paroxysmal character of the disease. Devor and colleagues state
      outright that no satisfactory animal model of trigeminal neuralgia exists.
    readouts:
    - name: Facial mechanical pain threshold
      target: Paroxysmal Neuralgiform Pain
      direction: DECREASED
      interpretation: >-
        A sustained threshold drop lasting weeks, which is a different
        behavioural pattern from the brief evoked paroxysms it is meant to model.
      evidence:
      - reference: PMID:27327156
        reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Behavioral tests showed that the mechanical pain threshold decreased significantly 4-42 days after surgery and reached the lowest observed value by day 12."
        explanation: The measured time course, which is sustained over weeks rather than paroxysmal.
    evidence:
    - reference: PMID:11803297
      reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "There are no satisfactory animal models of trigeminal neuralgia, and it is difficult to obtain essential data from patients."
      explanation: Substantiates the negative claim that no available animal model reproduces the human disease phenotype.
clinical_trials:
- name: NCT06620172
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Randomized comparison of CT-guided versus fluoroscopy-guided trigeminal
    ganglion radiofrequency thermocoagulation in idiopathic trigeminal
    neuralgia, with pain relief, medication consumption, and adverse events
    followed to six months.
  evidence:
  - reference: clinicaltrials:NCT06620172
    reference_title: "CT-guided vs Fluoroscopy-guided Trigeminal Ganglion Radiofrequency Thermocoagulation for Idiopathic Trigeminal Neuralgia: A Randomized Controlled Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Does CT-guided TG-RFT provide better pain relief compared to fluoroscopy-guided TG-RFT?"
    explanation: The trial's primary question, which concerns how the ablative procedure curated here is targeted.
- name: NCT05491915
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Multicenter case series of 60-day percutaneous peripheral nerve stimulation
    for occipital neuralgia and cervicogenic headache, relevant to the occipital
    subtype where refractory disease has few durable options.
  evidence:
  - reference: clinicaltrials:NCT05491915
    reference_title: "The MONARCH (Multicenter Occipital Neuralgia and Cervicogenic Headache) Case Series Study: Treatment of Head Pain With the SPRINT® Peripheral Nerve Stimulation (PNS) System"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to learn if pain can be relieved by delivering small amounts of electricity (called \"electrical stimulation\") to the nerves at the top of the neck."
    explanation: >-
      Describes stimulation of the upper cervical nerves, which are the nerves
      the occipital subtype involves. The registry title names occipital
      neuralgia as the study population.
discussions:
- discussion_id: gap_cn_ephaptic_mechanism_beyond_trigeminal
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the demyelination-and-ephaptic-cross-excitation mechanism, established for
    the trigeminal root, actually the mechanism in glossopharyngeal and nervus
    intermedius neuralgia, or is it assumed by analogy?
  attaches_to:
  - pathophysiology#Ectopic Discharge and Ephaptic Cross-Excitation
  rationale: >-
    The histopathology that grounds this entry's central mechanism comes from
    trigeminal nerve roots obtained at decompression surgery. Glossopharyngeal
    and nervus intermedius neuralgia are supported by operative observation of
    rootlet compression and by the fact that decompression relieves them, which
    is consistent with the same mechanism but does not demonstrate it — no
    comparable histological series of demyelination and axonal juxtaposition in
    those roots is available, and the operations are far rarer. Love and Coakham
    argue the generalisation explicitly, but on clinical and electrophysiological
    grounds rather than pathological ones. This matters for the concept decision
    recorded in this entry's notes: the case for one disease rather than a
    grouping rests on the generalisation holding.
  evidence:
  - reference: PMID:11701590
    reference_title: "Trigeminal neuralgia: pathology and pathogenesis."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical observations and electrophysiological studies support the concept that demyelination and ephaptic spread of excitation underlie most, if not all, of these conditions."
    explanation: >-
      The generalisation this gap questions, in the authors' own words. Note
      what it rests on -- clinical observation and electrophysiology, not the
      histology that grounds the trigeminal case.
  - reference: PMID:28263933
    reference_title: "Microvascular Decompression for Glossopharyngeal Neuralgia: Long-Term Follow-Up."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classic GPN is usually caused by pulsatile neurovascular compression of the glossopharyngeal and vagus rootlets."
    explanation: >-
      Operative observation of compression in the glossopharyngeal subtype,
      which is consistent with the shared mechanism but establishes the
      compression rather than the demyelination or the ephaptic step.
- discussion_id: gap_cn_compression_insufficient
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do most people with severe neurovascular contact never develop a
    neuralgia, and what determines which compressed nerves become symptomatic?
  attaches_to:
  - pathophysiology#Neurovascular Compression at the Nerve Root Entry Zone
  rationale: >-
    Neurovascular contact is present on 36% of asymptomatic nerves, and even
    severe contact appears on 13% of asymptomatic sides. Compression is
    therefore necessary-ish but plainly not sufficient, and the sex difference in
    how often severe contact explains the pain — 75% of men versus 38% of women
    — implies that a substantial fraction of disease, particularly in women, is
    driven by something this graph does not represent. Candidates have been
    proposed rather than the field being empty: a 2022 systematic review of the
    neurovascular compression syndromes lists demyelination, root-entry-zone
    remodelling, vasculature pathology, nucleus hyperexcitability, white- and
    grey-matter change, and ion-channel disturbance as changes that must coexist
    with the compression, and this entry's own STIM1/SOCE discussion and its C8B
    and MFGE8 susceptibility records point at an inflammatory background from a
    different direction. What is missing is not candidates but demonstration:
    none is established as the necessary second hit, and none has been shown to
    account for the sex difference specifically.
  evidence:
  - reference: PMID:27306631
    reference_title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurovascular contact was found in 471 out of 531 symptomatic nerves (89%) and 244 of 681 asymptomatic nerves (36%), indicating high sensitivity but poor specificity."
    explanation: Meta-analytic figures establishing that contact is common on asymptomatic nerves, which is the gap.
  - reference: PMID:25616608
    reference_title: "Association between neurovascular contact and clinical characteristics in classical trigeminal neuralgia: A prospective clinical study using 3.0 Tesla MRI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe NVC was much more prevalent in men than in women, who may more often have other disease etiologies causing or contributing to TN."
    explanation: >-
      The authors themselves infer from the sex difference that a substantial
      share of disease in women has a different aetiology, which is the
      unrepresented factor this gap names.
  - reference: PMID:35860499
    reference_title: "The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The systematic review suggests that the anatomical and/or hemodynamical changes described are insufficient to account for NVC-related symptoms by themselves. They must coexist with additional changes such as factors associated with the affected nerve (e.g., demyelination, REZ modeling, vasculature pathology), nucleus hyperexcitability, white and/or gray matter changes in the brain, or disturbances in ion channels."
    explanation: >-
      Systematic review of 63 papers stating both halves of this gap: that
      compression alone is insufficient, and which co-factors have been
      proposed. It is the source for rewording this rationale, which previously
      claimed no candidate had been proposed at all.
- discussion_id: gap_cn_stim1_soce_neuroinflammation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does STIM1/ORAI1 store-operated calcium entry and T-cell cytokine release
    contribute causally to human cranial neuralgia, or is the neuroinflammatory
    signal a consequence of nerve injury rather than a driver of it?
  attaches_to:
  - pathophysiology#Focal Demyelination and Axonal Juxtaposition
  rationale: >-
    A 2024 study reports STIM1 overexpression in trigeminal neuralgia patients
    by microarray reanalysis, and links STIM1-dependent store-operated calcium
    entry to TNF-alpha, IL-1beta, and IL-6 release from T lymphocytes in rat
    models. It is deliberately not modelled as a pathophysiology node here: the
    human component is bioinformatic reanalysis of deposited expression data
    rather than a measurement in patient tissue, the causal work is in the same
    rat constriction model this entry already flags as a poor human proxy, and
    nothing establishes direction -- immune activation around an injured nerve
    is expected downstream of demyelination, so finding it does not show it
    drives the disease. The complement and neuroinflammation genes in this
    entry's `genetic:` section point at the same unresolved question from a
    different direction, which is the reason to record it rather than drop it.
  evidence:
  - reference: DOI:10.3389/fnmol.2024.1391189
    reference_title: "Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression."
    explanation: >-
      The human-facing claim, which rests on reanalysis of deposited expression
      data rather than a measurement made in patients. Marked INDIRECT and graded
      COMPUTATIONAL for that reason, against the paper's own stronger wording.
  - reference: DOI:10.3389/fnmol.2024.1391189
    reference_title: "Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development."
    explanation: >-
      The mechanistic claim, made in rat models and in vitro. Marked INDIRECT
      because it does not establish that the pathway operates, or operates
      causally, in human disease.
- discussion_id: gap_cn_rodent_constriction_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do rodent nerve-constriction models reproduce the mechanism of human cranial
    neuralgia well enough for their sodium-channel findings to be transferred to
    it?
  attaches_to:
  - pathophysiology#Dysregulated Voltage-Gated Sodium Channel Expression
  rationale: >-
    The subunit-level detail in this entry's channel node comes from
    infraorbital-nerve chronic constriction injury in rats. That model injures a
    distal peripheral branch, whereas the human lesion is focal demyelination of
    the central, oligodendrocyte-myelinated segment of the root, and it produces
    sustained mechanical hypersensitivity rather than the triggered, paroxysmal,
    remitting pattern that defines the human disease. Devor and colleagues state
    plainly that there are no satisfactory animal models of trigeminal neuralgia
    and that the mechanistic account is a deduction awaiting patient data. The
    direction of change for individual channels should therefore be read as
    model-derived and not as a human finding.
  evidence:
  - reference: PMID:11803297
    reference_title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are no satisfactory animal models of trigeminal neuralgia, and it is difficult to obtain essential data from patients."
    explanation: States the model gap directly, and is why the mechanistic account in this entry is a deduction rather than a demonstration.
  - reference: PMID:27327156
    reference_title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Behavioral tests showed that the mechanical pain threshold decreased significantly 4-42 days after surgery and reached the lowest observed value by day 12."
    explanation: >-
      The model's readout is a sustained drop in mechanical threshold over
      weeks, not the triggered, brief, remitting paroxysms that define the human
      disease -- the specific behavioural mismatch this gap is about.
references:
- reference: PMID:11701590
  title: "Trigeminal neuralgia: pathology and pathogenesis."
- reference: PMID:11803297
  title: "Pathophysiology of trigeminal neuralgia: the ignition hypothesis."
- reference: PMID:27306631
  title: "Trigeminal neuralgia: New classification and diagnostic grading for practice and research."
- reference: PMID:30860637
  title: European Academy of Neurology guideline on trigeminal neuralgia.
- reference: PMID:31908187
  title: "Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments."
- reference: PMID:25541189
  title: Significance of neurovascular contact in classical trigeminal neuralgia.
- reference: PMID:25231219
  title: Trigeminal neuralgia--a prospective systematic study of clinical characteristics in 158 patients.
- reference: PMID:8598865
  title: The long-term outcome of microvascular decompression for trigeminal neuralgia.
- reference: PMID:2301931
  title: "Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945-1984."
- reference: PMID:1798429
  title: "Incidence and clinical features of glossopharyngeal neuralgia, Rochester, Minnesota, 1945-1984."
- reference: PMID:27017183
  title: "Prevalence of trigeminal neuralgia: A systematic review."
- reference: PMID:34986455
  title: "Prevalence of trigeminal neuralgia in multiple sclerosis: A systematic review and meta-analysis."
- reference: PMID:38575268
  title: Trigeminal and Glossopharyngeal Neuralgia.
- reference: PMID:28263933
  title: "Microvascular Decompression for Glossopharyngeal Neuralgia: Long-Term Follow-Up."
- reference: PMID:39847207
  title: Nervus Intermedius Neuralgia.
- reference: PMID:34287719
  title: Occipital Neuralgia.
- reference: PMID:24737457
  title: Occipital neuralgia.
- reference: PMID:39217283
  title: "An anatomical analysis of the occipital nerve complex: an essential tool for the application of occipital nerve blocks."
- reference: PMID:27327156
  title: "Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury."
- reference: PMID:27377706
  title: "Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials."
- reference: PMID:21998318
  title: "Increased risk of trigeminal neuralgia after hypertension: a population-based study."
- reference: PMID:25616608
  title: "Association between neurovascular contact and clinical characteristics in classical trigeminal neuralgia: A prospective clinical study using 3.0 Tesla MRI."
- reference: PMID:37144649
  title: Long-Term Efficacy of Gamma Knife Radiosurgery on Pain Control in Trigeminal Neuralgia.
- reference: PMID:38385643
  title: Long-term outcomes of Gamma Knife radiosurgery in treating glossopharyngeal neuralgia.
- reference: PMID:27102416
  title: Glossopharyngeal neuralgia associated with cardiac syncope.
- reference: PMID:26174508
  title: "Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study."
- reference: DOI:10.1007/s12031-024-02263-x
  title: Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia
- reference: DOI:10.1186/s12883-023-03415-z
  title: "Percutaneous radiofrequency thermocoagulation and microvascular decompression for treating glossopharyngeal neuralgia: a retrospective clinical study"
- reference: DOI:10.3389/fnmol.2024.1391189
  title: "Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia"
- reference: PMID:35860499
  title: "The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review."
- reference: PMID:30095334
  title: Nervus intermedius and the surgical management of geniculate neuralgia.
- reference: DOI:10.22514/jofph.2024.023
  title: "Autonomic features of craniofacial neuralgias: a systematic review with meta-analysis"
- reference: DOI:10.52965/001c.36042
  title: "Glossopharyngeal Neuralgia: Epidemiology, Risk factors,   Pathophysiology, Differential diagnosis, and Treatment Options  "

📚