Trigeminal Autonomic Cephalalgias
Trigeminal Autonomic Cephalalgias
What Do You Need to Know?
- TACs: unilateral headache + ipsilateral cranial autonomic features mediated by the trigeminal-parasympathetic reflex
- Cluster headache: male predominance (3–4:1), 15–180 min attacks, circadian/circannual periodicity; acute: 100% O2 12–15 L/min + sumatriptan 6 mg SC; preventive: verapamil (requires ECG monitoring)
- Paroxysmal hemicrania: female predominance, shorter attacks (2–30 min), >5/day, absolute indomethacin response (diagnostic criterion)
- SUNCT/SUNA: shortest attacks (1–600 sec), highest frequency (3–200/day), first-line treatment lamotrigine; must exclude pituitary adenoma
- Hemicrania continua: continuous unilateral headache with exacerbations + autonomic features; absolute indomethacin response (diagnostic criterion)
- Key differentiator: cluster = restlessness/pacing; migraine = lying still in dark
- Indomethacin-responsive TACs: PH and HC (NOT cluster)
TAC Overview & Pathophysiology
Trigeminal-Parasympathetic Reflex
- Afferent: V1 (ophthalmic) trigeminal afferents → trigeminal nucleus caudalis
- Central relay: trigeminal nucleus → superior salivatory nucleus (pons)
- Efferent: VII nerve parasympathetic outflow → pterygopalatine ganglion → cranial autonomic symptoms
- This reflex arc is the shared mechanism for autonomic features across all TACs
Hypothalamic Role
- Posterior hypothalamus = "pacemaker" — activated in cluster headache (PET, fMRI studies)
- Explains circadian (same time daily) and circannual (seasonal) periodicity
- Basis for deep brain stimulation (DBS) of posterior hypothalamus in refractory cluster
- Hypothalamic activation also seen in PH, SUNCT — suggests shared central generator
Cranial Autonomic Features
| Feature | Mechanism | Notes |
|---|---|---|
| Lacrimation | Parasympathetic (VII → lacrimal gland) | Most common autonomic feature |
| Conjunctival injection | Parasympathetic vasodilation | Key feature in SUNCT |
| Nasal congestion / rhinorrhea | Parasympathetic (VII → nasal mucosa) | Often misdiagnosed as "sinus headache" |
| Ptosis / miosis | Sympathetic dysfunction (partial Horner) | Can become persistent between attacks |
| Eyelid edema | Parasympathetic vasodilation + venous congestion | Ipsilateral only |
| Forehead / facial sweating | Sympathetic dysfunction | Ipsilateral to pain |
💎 Board Pearl
- All TACs are strictly unilateral — bilateral pain should prompt reconsideration of the diagnosis
- Partial Horner syndrome (ptosis + miosis without anhidrosis) can persist between cluster periods — do NOT mistake for a new Horner requiring workup
Cluster Headache
ICHD-3 Diagnostic Criteria
- Pain: severe to very severe, unilateral, orbital/supraorbital/temporal
- Duration: 15–180 minutes (untreated)
- Frequency: 1 every other day to 8 per day
- ≥1 ipsilateral autonomic feature OR sense of restlessness/agitation
- ≥5 attacks fulfilling criteria
Subtypes
| Subtype | Definition |
|---|---|
| Episodic cluster | ≥2 cluster periods lasting 7 days–1 year, separated by remission ≥3 months |
| Chronic cluster | No remission period ≥3 months for ≥1 year (or remissions <3 months) |
Epidemiology & Clinical Features
- Male:female = 3–4:1 (most male-predominant primary headache)
- Onset typically age 20–40 years
- Strong association with smoking (up to 65% of patients)
- Circadian periodicity: attacks at same time daily, often nocturnal (1–2 AM) — "alarm clock headache"
- Circannual periodicity: cluster bouts in spring and fall
- Restlessness/agitation: pacing, rocking, head banging — key distinction from migraine (where patients lie still in dark)
- Alcohol triggers attacks only during a cluster period (not during remission)
Acute Treatment
| Treatment | Dose / Route | Details |
|---|---|---|
| 100% O2 | 12–15 L/min via non-rebreather | First-line; 78% response within 15 min; no side effects; no contraindications |
| Sumatriptan SC | 6 mg subcutaneous | First-line pharmacologic; fastest triptan onset (5–15 min); can repeat ×1 in 24 h |
| Zolmitriptan intranasal | 5 mg nasal spray | Alternative to SC sumatriptan; effective within 15–30 min |
| Lidocaine intranasal | 4–10% ipsilateral nostril | Adjunctive; targets sphenopalatine ganglion |
Transitional (Bridge) Therapy
- Prednisone burst: 60–100 mg/day ×5 days, then taper over 2–3 weeks
- Greater occipital nerve (GON) block: suboccipital injection of local anesthetic ± corticosteroid
- Purpose: rapid suppression while waiting for preventive agents to reach therapeutic effect
Preventive Treatment
| Agent | Details | Monitoring |
|---|---|---|
| Verapamil | First-line preventive; doses often 240–960 mg/day; slow titration | ECG before initiation and with every dose increase (PR prolongation, AV block) |
| Lithium | More effective for chronic cluster; 600–1200 mg/day | Lithium levels, renal function, thyroid |
| Galcanezumab | FDA-approved for episodic cluster (300 mg SC monthly); only CGRP mAb with this indication | Injection site reactions |
| Topiramate | Third-line; 100–200 mg/day | Cognitive effects, kidney stones, weight loss |
| Melatonin | 10 mg at bedtime; adjunctive; reflects hypothalamic mechanism | Minimal side effects |
💎 Board Pearl
- Verapamil requires ECG monitoring with each dose increase — risk of PR prolongation and heart block; doses in cluster often exceed standard cardiology doses
- Cluster headache + restlessness/agitation = key distinguishing feature from migraine (patients pace, rock, or bang head)
- Galcanezumab is the only FDA-approved CGRP mAb for episodic cluster headache
Clinical Pearl
- Oral triptans are generally too slow for cluster attacks (15–180 min duration) — always use SC sumatriptan or intranasal zolmitriptan
- Cluster patients frequently present to the ER — high-flow O2 should be tried before opioids (which are ineffective)
Paroxysmal Hemicrania (PH)
ICHD-3 Diagnostic Criteria
- Pain: severe, unilateral, orbital/supraorbital/temporal
- Duration: 2–30 minutes per attack
- Frequency: >5 attacks per day (average 11–14/day)
- ≥1 ipsilateral autonomic feature
- Absolute response to therapeutic doses of indomethacin (diagnostic criterion)
Key Features
- Female predominance (unlike cluster)
- Subtypes: episodic PH and chronic PH (same temporal criteria as cluster)
- Indomethacin therapeutic trial: start 25 mg TID, increase to 50–75 mg TID (max 225 mg/day)
- Response is typically dramatic and complete within 1–2 days
- If indomethacin is not tolerated: celecoxib, topiramate, or verapamil may provide partial relief
PH vs. Cluster: Side-by-Side
| Feature | Paroxysmal Hemicrania | Cluster Headache |
|---|---|---|
| Duration | 2–30 min | 15–180 min |
| Frequency | >5/day (often 11–14) | 1 every other day to 8/day |
| Sex predominance | Female | Male (3–4:1) |
| Indomethacin | Absolute response (required for diagnosis) | No response |
| O2 / sumatriptan | Not effective | First-line acute |
| Preventive | Indomethacin (continuous) | Verapamil |
| Restlessness | Less prominent | Hallmark feature |
💎 Board Pearl
- Indomethacin-responsive = PH or HC — NOT cluster headache
- Short attacks + high frequency + female + indomethacin response = PH (not cluster)
- If a "cluster headache" responds to indomethacin, reclassify as PH
SUNCT & SUNA
Definitions
- SUNCT: Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection AND Tearing
- SUNA: Short-lasting Unilateral Neuralgiform headache attacks with cranial Autonomic symptoms — only one or neither of conjunctival injection/tearing
ICHD-3 Criteria
- Duration: 1–600 seconds (typically 5–240 seconds)
- Frequency: ≥1/day; can be 3–200+ attacks/day (highest frequency of all TACs)
- Moderate to severe unilateral pain, orbital/supraorbital/temporal
- ≥1 ipsilateral autonomic feature
Key Clinical Features
- Cutaneous triggers: light touch to face, chewing, brushing teeth, wind — mimics trigeminal neuralgia
- Unlike TN: no refractory period between attacks
- Must exclude pituitary adenoma — MRI with dedicated sella views required in all SUNCT/SUNA patients
- Can also be secondary to posterior fossa or CPA lesions
SUNCT/SUNA vs. Trigeminal Neuralgia
| Feature | SUNCT/SUNA | Trigeminal Neuralgia |
|---|---|---|
| Duration | 1–600 sec | Fraction of a second to 2 min |
| Autonomic features | Prominent (required) | Absent or mild |
| Distribution | V1 (orbital/supraorbital) | V2/V3 (maxillary/mandibular) |
| Refractory period | None | Present (seconds to minutes) |
| Background pain | Often present between attacks | Typically pain-free between attacks |
| Carbamazepine response | Poor | Excellent (first-line) |
| First-line treatment | Lamotrigine | Carbamazepine |
Treatment
- Lamotrigine: first-line (slow titration to 200–400 mg/day)
- Topiramate: second-line
- Carbamazepine/oxcarbazepine: may help SUNA (less effective in SUNCT)
- Gabapentin: adjunctive
- IV lidocaine: for refractory/acute exacerbations (ICU setting)
- Indomethacin, O2, and triptans are NOT effective
💎 Board Pearl
- SUNCT/SUNA = shortest duration + highest frequency of all TACs
- Always order MRI sella in suspected SUNCT/SUNA — pituitary adenoma is a known secondary cause
- V1 distribution + autonomic features + no refractory period = SUNCT/SUNA (not TN)
Hemicrania Continua (HC)
ICHD-3 Diagnostic Criteria
- Continuous unilateral headache (no pain-free periods) for >3 months
- Fluctuating intensity with moderate to severe exacerbations
- During exacerbations: ≥1 ipsilateral autonomic feature AND/OR restlessness/agitation
- Absolute response to therapeutic doses of indomethacin (diagnostic criterion)
Key Clinical Features
- Baseline = continuous low-grade unilateral pain
- Superimposed exacerbations with autonomic features (lacrimation, conjunctival injection, ptosis/miosis, rhinorrhea)
- Exacerbations can mimic migraine features (photophobia, phonophobia, nausea)
- Side-locked: pain always on the same side (does NOT alternate)
- Can be remitting or unremitting subtypes
Indomethacin Trial
- Start 25 mg TID, increase to 50–75 mg TID over 1–2 weeks
- Dramatic and complete resolution of headache expected
- Intramuscular indomethacin 50 mg (the "indotest") can provide rapid diagnostic confirmation
- If indomethacin not tolerated: melatonin (9–18 mg), topiramate, celecoxib, or GON block as alternatives (partial relief)
Differential Diagnosis
| Condition | Key Distinguishing Features |
|---|---|
| Chronic migraine | Can alternate sides; no absolute indomethacin response; ≥15 headache days/month |
| NDPH | Daily from onset; often bilateral; no indomethacin response; no autonomic features |
| Chronic cluster | Distinct attacks with pain-free intervals; does NOT have continuous baseline |
💎 Board Pearl
- Continuous unilateral headache + autonomic exacerbations + indomethacin response = hemicrania continua
- HC is the only TAC with a continuous baseline pain component
- If pain switches sides → diagnosis is NOT HC (must be side-locked)
Master Comparison Table
| Feature | Cluster | Paroxysmal Hemicrania | SUNCT/SUNA | Hemicrania Continua |
|---|---|---|---|---|
| Sex predominance | Male (3–4:1) | Female | Male (slight) | Female (slight) |
| Pain duration | 15–180 min | 2–30 min | 1–600 sec | Continuous + exacerbations |
| Attack frequency | 1 q.o.d. to 8/day | >5/day | 3–200/day | N/A (continuous) |
| Autonomic features | Yes | Yes | Yes (prominent) | Yes (during exacerbations) |
| Restlessness | Hallmark | Less prominent | No | During exacerbations |
| Circadian pattern | Yes (nocturnal, 1–2 AM) | No | No | No (continuous) |
| Acute treatment | O2, sumatriptan SC | Indomethacin | IV lidocaine (refractory) | Indomethacin |
| Preventive treatment | Verapamil, lithium, galcanezumab | Indomethacin (continuous) | Lamotrigine, topiramate | Indomethacin (continuous) |
| Indomethacin response | No | Absolute (diagnostic) | No | Absolute (diagnostic) |
| Key distinguishing feature | Circadian periodicity + restlessness | Short attacks + high frequency + indo response | Ultrashort + very high frequency + cutaneous triggers | Continuous baseline + indo response |
Clinical Pearl
- When evaluating a unilateral headache with autonomic features, attack duration is the single most useful feature for distinguishing TAC subtype: seconds = SUNCT/SUNA; minutes = PH; hours = cluster; continuous = HC
- If in doubt, trial of indomethacin (150–225 mg/day for ≥3 days) is both therapeutic and diagnostic for PH and HC
References
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
- May A, Schwedt TJ, Magis D, et al. Cluster headache. Nat Rev Dis Primers. 2018;4:18006.
- Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141.
- Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA) — a prospective clinical study of SUNCT and SUNA. Brain. 2006;129(10):2746-2760.
- Cittadini E, Goadsby PJ. Hemicrania continua: a clinical study of 39 patients with diagnostic implications. Brain. 2010;133(7):1973-1986.
- Robbins MS, Starling AJ, Pringsheim TM, et al. Treatment of cluster headache: the American Headache Society evidence-based guidelines. Headache. 2016;56(7):1093-1106.