Trigeminal neuralgia

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Trigeminal Neuralgia

Definition

Trigeminal neuralgia (TN) is a paroxysmal pain disorder felt within the distribution of one or more divisions of the trigeminal nerve (CN V). It is one of the most intensely painful conditions known to medicine.

Classification (ICHD-3)

Type	Description
Classical TN	Vascular compression of the trigeminal nerve root (confirmed on MRI or surgery), with associated nerve root atrophy or displacement
Secondary TN	Due to an underlying disease - most commonly multiple sclerosis or a space-occupying lesion; may have both paroxysmal and continuous pain
Idiopathic TN	No causative lesion and no morphological change attributable to vessel contact

Epidemiology

Incidence: ~4 per 100,000
Age: 90% of cases begin after age 40; incidence rises with age
Sex: slightly more common in women (F:M ~1.5:1)
Rare familial cases suggest a genetic contribution in some families
In younger patients, consider multiple sclerosis as a secondary cause

Pathogenesis

The dominant mechanism is neurovascular compression at the trigeminal nerve root entry zone, most often by the superior cerebellar artery, but also the anterior/posterior inferior cerebellar arteries, or superior petrosal vein. Chronic vascular pulsation produces focal demyelination of primary trigeminal afferents near where the nerve enters the pons. This demyelination is hypothesized to cause:

Focal hyperexcitability of axons
Ectopic neuronal discharges
Ephaptic transmission between adjacent demyelinated fibers

In MS-related TN, demyelinating plaques in the pons at the nerve root entry zone produce the same effect through the same mechanism.

Clinical Features

Pain Characteristics

Quality: Electric shock-like, shooting, lancinating - described as one of the most severe pains known
Duration: Seconds per attack (up to 2 minutes); attacks may cluster so closely they blur together
Location: V2 (cheek, upper lip, upper teeth) and V3 (chin, lower lip, lower teeth) most common; the combination V2+V3 is most frequent. V1 alone is extremely rare.
Laterality: Unilateral; bilateral is very rare
Refractory period: After an attack, a brief refractory period occurs during which pain cannot be triggered

Triggers

Touch to skin, mucosa, or teeth within the trigeminal distribution - especially:

Touching/washing the face
Brushing teeth
Chewing or swallowing
Talking
Cool breeze across the face
The trigger zone most commonly occurs near the nasolabial fold, which may be remote from the actual pain site

Key Negative Features (Classical TN)

No sensory loss - sensory examination is normal
No motor weakness of masticatory muscles
Attacks during sleep are uncommon

Sensory impairment or masticatory weakness suggests secondary TN (trigeminal neuropathy), pointing to a lesion at the gasserian ganglion, main sensory root, or root entry zone.

Systemic Consequences

Frequent attacks may lead to weight loss, dehydration, or depression due to fear of triggering pain.

Diagnosis

Diagnosis is clinical. Key criteria:

Paroxysmal attacks lasting 1 second to 2 minutes
Intensely sharp, stabbing quality OR precipitated by a trigger
Distribution along one or more trigeminal divisions
Stereotypical attacks
No neurological deficits (in classical TN)

MRI is recommended in all patients to exclude secondary causes:

MS demyelinating plaque at the pons
Pontine lacunar infarct
Meningioma or schwannoma of the posterior fossa
Malignant skull base infiltration
High-resolution MRI/MRA can identify neurovascular contact

Differential Diagnosis

Trigeminal autonomic cephalalgias (have autonomic features: ptosis, lacrimation, rhinorrhea)
Atypical facial pain / persistent idiopathic facial pain
Idiopathic stabbing headache
Tolosa-Hunt syndrome (inflammatory cavernous sinus lesion)
Dental or temporomandibular joint pathology
Glossopharyngeal neuralgia (pain in throat, tonsil, ear - triggered by swallowing)

Treatment

Medical (First-Line)

Sodium channel blockers are the drugs of choice:

Drug	Dose	Notes
Carbamazepine	600-1200 mg/day (start 50-100 mg, titrate slowly)	First-line; highly favorable response in majority; monitor CBC, LFTs, Na
Oxcarbazepine	300-1800 mg/day	Better tolerated; risk of significant hyponatremia

Start carbamazepine at low doses (50-100 mg) and increase slowly - especially in elderly - to avoid vertigo, drowsiness, and ataxia. Taper once pain is controlled to detect spontaneous remission.

Second-line agents (alone or in combination):

Gabapentin (900-1800 mg) - benign side-effect profile; reasonable alternative to CBZ
Pregabalin
Baclofen (50-60 mg)
Phenytoin (200-300 mg)
Lamotrigine (100-400 mg)
Valproate, clonazepam, topiramate
Botulinum toxin injection (emerging evidence)

Acute severe attack: IV fosphenytoin 15-20 mg PE/kg; or topical proparacaine to the ipsilateral conjunctival sac (can provide relief for hours to days).

Surgical (for medical refractory patients)

Three main categories:

1. Percutaneous procedures (targeting gasserian ganglion via foramen ovale):

Radiofrequency thermocoagulation
Glycerol rhizolysis (chemical destruction)
Balloon compression
Preferred in elderly or medically complex patients - easier to perform, good short-term relief

2. Stereotactic radiosurgery:

Gamma Knife radiosurgery targeting the trigeminal root
Non-invasive but delayed onset of effect (weeks to months)
A 2025 meta-analysis (PMID 41108438) assessed repeated radiosurgery for refractory/recurrent TN with favorable outcomes

3. Microvascular decompression (MVD):

Posterior fossa craniotomy; separates the offending vessel from the nerve using a Teflon pad
Most durable results, preserves sensory function
Preferred for younger, healthy patients
A 2025 meta-analysis (PMID 40889405) reviewed second-line strategies after MVD failure

Peripheral nerve blocks:

Alcohol injection of the mental, infraorbital, or supraorbital nerve branch
Relief in a high proportion but relapse likely within 6-18 months
Can be repeated once or twice before a more definitive proximal procedure is needed

Surgical decision framework:

Young, healthy patient + refractory to medical therapy → MVD (durable, preserves sensation)
Elderly or high surgical risk → Percutaneous ganglion procedure (less invasive)
Treatment must be individualized to patient's age, comorbidities, and preference

Course and Prognosis

TN typically has an exacerbating-remitting course over many years. During exacerbations, attacks may occur many times daily for weeks to months. Spontaneous remissions can occur at any time and last months to years. The reasons for these fluctuations are unknown.

Sources: Bradley and Daroff's Neurology in Clinical Practice; Goldman-Cecil Medicine, 26th ed.

Headache under evaluation

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Headache Under Evaluation

Step 1: The Fundamental Question - Primary vs. Secondary

The first decision in evaluating any headache is determining whether it is primary (the headache disorder itself is the disease) or secondary (headache is a symptom of an underlying condition). This distinction drives urgency, workup, and management.

"The patient who presents with a new, severe headache has a differential diagnosis that is quite different from the patient with recurrent headaches over many years. In new-onset and severe headache, the probability of finding a potentially serious cause is considerably greater."

Harrison's Principles of Internal Medicine, 22nd ed.

Step 2: Red Flags (SNOOP Approach)

Red flags mandate urgent investigation. The following features suggest a dangerous secondary cause:

#	Red Flag	Possible Etiology
1	Thunderclap headache - maximal intensity within <5 min	Subarachnoid hemorrhage, reversible cerebral vasoconstriction syndrome
2	"Worst headache of my life" / first severe headache	SAH, intracranial hemorrhage
3	Progressively worsening headache over days/weeks	Mass lesion, subdural hematoma, ICP
4	Fever + neck stiffness	Meningitis, encephalitis
5	Abnormal neurological examination	Mass, hemorrhage, stroke
6	New focal neurological symptoms	Intracranial pathology
7	Altered mental status	Meningitis, encephalitis, severe ICP
8	Papilledema (optic disc edema)	Raised ICP
9	Pain with Valsalva / bending / lifting / cough	Posterior fossa mass, Chiari malformation, low CSF pressure
10	Pain waking from sleep or immediately on awakening	Raised ICP, posterior fossa tumor
11	Vomiting preceding headache (by weeks)	Posterior fossa tumor
12	Onset after age 55	Giant cell arteritis, mass lesion
13	Temporal artery tenderness	Giant cell (temporal) arteritis
14	Immunocompromised / on anticoagulation	Opportunistic infection, hemorrhage
15	Seizures	Intracranial lesion
16	Visual symptoms atypical for migraine (diplopia, field deficits, decreased acuity)	ICP, arteritis, mass
17	Known systemic malignancy	Cerebral metastases, carcinomatous meningitis
18	Signs of endocrine pathology	Pituitary adenoma

Step 3: Classification of Headache (ICHD-3 Framework)

Primary Headaches

Type	Key Features	Duration	Associated Symptoms
Migraine	Unilateral/bilateral; throbbing; moderate-severe; worsens with activity; complex genetics, family history; more common in women	Hours to days	Photophobia, phonophobia, nausea/vomiting; may have aura
Tension-type	Tight band-like, bilateral; mild-moderate; improves with activity; family history	Hours to days	No nausea/vomiting; mild photo or phonophobia (not both)
Cluster headache	Unilateral, severe, periorbital/temporal; 4x more common in men; posterior hypothalamic activation	30-90 min; occurs in clusters	Ipsilateral ptosis, miosis, lacrimation, rhinorrhea, eyelid edema
Paroxysmal hemicrania	Unilateral facial pain; more common in women	Minutes	Ipsilateral autonomic features; responds to indomethacin
Hemicrania continua	Unilateral, continuous + episodic stabs; more common in women	Continuous	Ipsilateral autonomic features; responds to indomethacin
SUNCT/SUNA	Unilateral orbital/periorbital; more common in men	Seconds to 240 s	Conjunctival injection, tearing

Secondary Headaches (Key Causes)

Vascular:

Subarachnoid hemorrhage (ruptured aneurysm, AVM) - thunderclap; LP required if CT negative
Intracranial hemorrhage (epidural, subdural, intraparenchymal)
Carotid/vertebral artery dissection
Cerebral venous sinus thrombosis
Reversible cerebral vasoconstriction syndrome (RCVS)
Giant cell (temporal) arteritis - age >50, jaw claudication, ESR elevated; risk of blindness

Infectious/Inflammatory:

Meningitis - fever, stiff neck, photophobia; LP mandatory
Encephalitis
Sinusitis, dental abscess

Structural/Pressure:

Brain tumor (~30% have headache as chief complaint; usually dull, intermittent, worse with exertion; only disturbs sleep in ~10%)
Idiopathic intracranial hypertension (pseudotumor cerebri) - obesity, female, papilledema, pulsatile tinnitus
Low CSF pressure (post-LP, spontaneous leak) - orthostatic headache (worse upright, better supine)
Hydrocephalus
Chiari malformation (headache with Valsalva/cough)

Metabolic/Toxic:

Hypertensive crisis
CO poisoning
Medication/drug effects, caffeine withdrawal
Hypoxia (sleep apnea)

Other:

Post-traumatic headache
Glaucoma (eye pain, red eye, fixed mid-dilated pupil, nausea)
Referred pain from cervical spine, TMJ, sinuses, teeth

Step 4: The History - Key Questions

A structured history is the most powerful diagnostic tool:

Domain	Ask About
Onset	Sudden ("thunderclap") vs. gradual; first-ever vs. recurrent
Time course	Duration, frequency, pattern (episodic vs. chronic daily)
Quality	Throbbing, stabbing, pressure/band-like, boring
Location	Unilateral vs. bilateral; fronto-temporal, occipital, periorbital
Severity	VAS 1-10; functional impairment
Associated features	Nausea/vomiting, photo/phonophobia, aura, autonomic symptoms, fever, neck stiffness
Triggers	Stress, menses, sleep changes, food, alcohol, Valsalva
Relieving factors	Rest, darkness, sleep, activity
Medications	Analgesic use frequency (>10-15 days/month = medication overuse risk)
Systemic	Weight loss, fever, malignancy, HIV/immunosuppression
Family history	Migraine, SAH
Psychological	Depression, anxiety (comorbid with headache; treat both)

Step 5: Physical Examination

A full neurological exam is essential for every new headache patient.

Key elements:

Meningism - nuchal rigidity, Kernig's sign, Brudzinski's sign
Fundoscopy - papilledema (raised ICP), hypertensive retinopathy
Blood pressure - hypertensive urgency/emergency
Temporal artery palpation - tenderness, nodularity, absence of pulse (temporal arteritis)
Cranial nerve examination - especially II, III, VI (mass effect, herniation)
Cerebellar signs - posterior fossa lesion
Intraocular pressure - if glaucoma suspected

Step 6: Investigations

Neuroimaging

CT head (non-contrast) - first choice for acute severe headache; rules out hemorrhage, hydrocephalus
MRI brain - more sensitive for mass, demyelination, venous thrombosis, Chiari; preferred for subacute/chronic
CT/MR angiography - for suspected aneurysm, dissection, RCVS
MR venography - for suspected cerebral venous sinus thrombosis

CT and MRI are equally sensitive as initial screening for intracranial pathology in the acute setting. - Harrison's

Lumbar Puncture

Indicated when SAH suspected and CT is normal (xanthochromia in CSF confirms SAH)
Indicated for suspected meningitis/encephalitis
Opening pressure required (elevated in IIH, low in CSF leak)
Cell count, glucose, protein, culture, cytology as indicated

Blood Tests

ESR + CRP - giant cell arteritis (in any new headache over age 50)
CBC - infection, anemia
Metabolic panel - electrolytes, glucose, renal function
Urine - renal disease, porphyria
Blood cultures - if septic meningitis suspected

Step 7: Chronic Daily Headache (CDH)

Defined as headache on ≥15 days/month. Not a single diagnosis - encompasses:

Primary CDH (>4 h/day)	Primary CDH (<4 h/day)	Secondary CDH
Chronic migraine	Chronic cluster headache	Posttraumatic
Chronic tension-type	Chronic paroxysmal hemicrania	Inflammatory (GCA, sarcoid, Behçet)
Hemicrania continua	SUNCT/SUNA	Chronic CNS infection
New daily persistent headache	Hypnic headache	Medication overuse headache

Medication Overuse Headache (MOH)

Analgesics used on >10-15 days/month can transform episodic to chronic headache
Opioids and barbiturates carry highest risk
Management: gradual taper (reduce by 10% every 1-2 weeks) or abrupt cessation; bridge with naproxen 500 mg twice daily

Step 8: Management Principles by Category

Headache Type	Acute Treatment	Prevention
Migraine	NSAIDs, triptans (5HT1B/D agonists), ditans (5HT1F), gepants (CGRP antagonists), anti-emetics	Beta-blockers, topiramate, valproate, amitriptyline, CGRP monoclonal antibodies
Tension-type	NSAIDs, paracetamol	Amitriptyline/nortriptyline, NSAIDs
Cluster	Oxygen (100%), sumatriptan SC/intranasal	Verapamil, lithium, topiramate, short-course steroids
GCA	High-dose glucocorticoids urgently (prevent blindness)	Long-term steroid taper ± tocilizumab
IIH	Acetazolamide, weight loss; LP as temporizing measure	Acetazolamide; shunting/optic nerve fenestration if vision threatened
MOH	Withdraw offending analgesic	Address underlying primary headache
Secondary	Treat underlying cause	-

For medically refractory primary headache, neuromodulation options include single-pulse transcranial magnetic stimulation (sTMS), non-invasive vagal nerve stimulation (nVNS - especially cluster and TACs), and remote electrical neuromodulation.

Sources: Harrison's Principles of Internal Medicine, 22nd ed.; Goldman-Cecil Medicine, 26th ed.; Harriet Lane Handbook, 23rd ed.; Neuroanatomy through Clinical Cases, 3rd ed.

Dosages of these drugs given in the table

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Headache Drug Dosages

Based on the preventive medications table (Goldman-Cecil, Table 367-4), acute treatment dosages, and triptan pharmacokinetics (Katzung, Table 16-6).

ACUTE TREATMENT DRUGS

Mild-Moderate Attacks

Drug	Dose	Notes
Paracetamol (Acetaminophen)	650-1000 mg	OTC; first-line for mild attacks
Aspirin	250-1000 mg
Ibuprofen	400-600 mg (acute migraine); 600-800 mg bid-tid (prevention)
Naproxen	500-825 mg (acute); 200-600 mg/day (prevention)	Also used for menstrual migraine
Diclofenac	50 mg
Ketoprofen	75 mg
Ketorolac	60 mg IM or 30 mg IV	For severe attacks; rescue therapy

Triptans (5-HT1B/D Agonists) - Moderate-Severe Attacks

Drug	Route	Single Dose	Max/Day	Onset	Half-Life
Sumatriptan	Oral	25-100 mg	200 mg	~1.5 h	2 h
Sumatriptan	Subcutaneous	6 mg SC	-	~12 min (fastest)	2 h
Sumatriptan	Nasal spray	20 mg	-	-	2 h
Sumatriptan	Rectal	25 mg	-	-	2 h
Zolmitriptan	Oral/nasal	2.5-5 mg	10 mg	1.5-3 h	2.8 h
Rizatriptan	Oral	5-10 mg	30 mg	1-2.5 h	2 h
Eletriptan	Oral	20-40 mg	80 mg	2 h	4 h
Almotriptan	Oral	6.25-12.5 mg	25 mg	2.6 h	3.3 h
Naratriptan	Oral	1-2.5 mg	5 mg	2 h	5.5 h
Frovatriptan	Oral	2.5 mg	7.5 mg	3 h	27 h (longest)

Contraindications for triptans: Uncontrolled hypertension, ischemic heart disease, Prinzmetal angina. Sumatriptan SC 6 mg has the fastest onset (12 min) - best for rapid, severe attacks. Frovatriptan has the longest half-life - useful for menstrual migraine prophylaxis.

Ditans (5-HT1F Agonist) - Safe When Triptans Contraindicated

Drug	Dose	Notes
Lasmiditan	50-200 mg orally	No vasoconstrictive effect; driving contraindicated for ≥8 h post-dose

Gepants (CGRP Receptor Antagonists) - Acute Use

Drug	Dose	Notes
Rimegepant	75 mg orally (ODT)	Every other day (qod); also approved for prevention
Ubrogepant	50-100 mg orally	~10% absolute increase in 2-h pain freedom vs placebo

Ergot Derivatives

Drug	Route	Dose
Dihydroergotamine (DHE)	Intranasal or SC	1-2 mg
DHE	IV (severe attacks)	0.5-1 mg IV + antiemetic
Ergotamine tartrate	Sublingual	2 mg
Ergotamine tartrate	Oral	1-2 mg

Antiemetics / Rescue (Dopamine Antagonists)

Drug	Dose	Notes
Prochlorperazine	10-25 mg IM or 10 mg IV over 5 min	Very effective for severe attacks
Metoclopramide	10 mg IV	Prokinetic + antiemetic
Promethazine	25 mg	Required before IV DHE

Cluster Headache - Acute

Drug	Dose	Notes
100% Oxygen	7-10 L/min for 15-30 min	Non-rebreathing mask; first-line
Sumatriptan SC	4-6 mg SC	Fast-acting; A-level evidence
Sumatriptan nasal	20 mg intranasal	A-level evidence
Zolmitriptan nasal	5 mg intranasal	A-level evidence
DHE	Nasal, IM, or IV	Alternative

PREVENTIVE (PROPHYLACTIC) DRUGS

Beta-Blockers

Drug	Dose	Use	Side Effects	Contraindications
Propranolol	20-80 mg (may increase)	Migraine; hypertension	Lethargy, depression	Asthma, hypotension
Nadolol	Titrate	Migraine	Lethargy	Asthma
Timolol	Titrate	Migraine	Lethargy	Asthma

Calcium-Channel Blockers

Drug	Dose	Use	Side Effects
Verapamil	120-480 mg/day (episodic); 240-480 mg (cluster prevention)	Cluster headache (first choice), migraine; hypertension	Hypotension, constipation
Amlodipine	Titrate	Migraine	Hypotension

NSAIDs (Preventive)

Drug	Dose	Use
Naproxen	200-600 mg/day	Migraine, tension-type, menstrual migraine
Ibuprofen	600-800 mg bid-tid	Migraine, tension-type
Indomethacin	25-50 mg tid	Paroxysmal hemicrania, hemicrania continua (A-level; diagnostic - complete response confirms diagnosis)

Tricyclic Antidepressants

Drug	Dose	Use	Side Effects
Amitriptyline	Start 10-25 mg qhs; titrate up to 1 mg/kg or 100 mg	Migraine, tension-type, poor sleep; CDH	Dry mouth, orthostatic hypotension, weight gain
Nortriptyline	25-100 mg each evening	Migraine, tension-type	Fewer anticholinergic effects than amitriptyline
Imipramine	Titrate from 10-25 mg qhs	Migraine	As above

Anticonvulsants

Drug	Dose	Use	Side Effects	Caution
Topiramate	25-50 mg bid	Migraine, cluster	Weight loss, kidney stones, intraocular hypertension, cognitive impairment	FDA Category D (pregnancy)
Valproate	250-500 mg bid	Migraine, cluster	Weight gain, teratogenicity	FDA Category D (pregnancy)
Gabapentin	300-1800 mg/day	SUNCT/SUNA (B-level)	Sedation	-
Lamotrigine	Titrate	SUNCT/SUNA (B-level)	Rash	-

CGRP Monoclonal Antibodies (Preventive)

Drug	Target	Dose	Frequency
Eptinezumab	CGRP ligand	120-300 mg IV	Every 3 months
Erenumab	CGRP receptor	70-140 mg SC	Monthly
Fremanezumab	CGRP ligand	225 mg SC	Monthly
Galcanezumab	CGRP ligand	240 mg SC loading, then 120 mg SC	Monthly (also for episodic cluster: 300 mg SC monthly)

Side effects: Injection-site reactions, nasal symptoms, constipation. Pregnancy safety unknown.

CGRP Receptor Antagonists (Gepants - Preventive/Acute)

Drug	Dose	Use
Rimegepant	75 mg orally every other day	Migraine prevention and acute treatment
Atogepant	10-30 mg orally daily	Migraine prevention

Cluster Prevention (Additional)

Drug	Dose	Notes
Verapamil	240-480 mg/day	Drug of choice for cluster prevention
Lithium	300 mg bid	Alternative to verapamil
Prednisone (bridge)	40-100 mg/day x 5 days, then taper over 3 days	Short-term bridge while starting prophylaxis
Dexamethasone (bridge)	4 mg bid x 2 weeks	Alternative corticosteroid bridge
Galcanezumab	300 mg SC monthly	A-level evidence for episodic cluster

Sources: Goldman-Cecil Medicine, 26th ed. (Table 367-4, 367-5); Katzung's Basic & Clinical Pharmacology, 16th ed. (Table 16-6); Harrison's Principles of Internal Medicine, 22nd ed.

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