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Summary Table

Category	Details
Risk Factors	Male sex (male-to-female ratio approximately 3:1 to 4:1), age 20 to 40 years, tobacco use, alcohol consumption (triggers attacks during a cluster period), family history
Etiology	Hypothalamic dysfunction with activation of the trigeminovascular system and parasympathetic outflow; not fully understood but involves circadian rhythm disruption
Patient Presentation	Severe, strictly unilateral periorbital or temporal pain lasting 15 to 180 minutes, occurring in bouts (clusters) of weeks to months, often at the same time each day, frequently waking the patient from sleep
Classic Physical Exam	Ipsilateral conjunctival injection, lacrimation, nasal congestion or rhinorrhea, eyelid edema, forehead/facial sweating, miosis, ptosis; patient is restless and agitated (pacing, rocking) rather than lying still
Key Diagnostic Results	Clinical diagnosis based on ICHD-3 criteria; neuroimaging (MRI brain with contrast) is used to exclude secondary causes, not to confirm the diagnosis
Management	Acute: high-flow 100% oxygen via non-rebreather mask and/or subcutaneous sumatriptan. Preventive (transitional): short-course oral corticosteroids. Preventive (maintenance): verapamil
Keywords	"Suicide headache," "alarm clock headache," restlessness/agitation during attack, ipsilateral autonomic features, circadian periodicity, male smoker

1. Pathophysiology

Cluster headache is classified as a trigeminal autonomic cephalalgia (TAC), a group of primary headache disorders characterized by unilateral head pain accompanied by ipsilateral cranial autonomic symptoms. The pathophysiology centers on the posterior hypothalamus, which acts as the pacemaker driving the cyclical and clock-like nature of attacks. Functional imaging studies consistently demonstrate activation of the ipsilateral posterior hypothalamic gray matter during cluster attacks, which explains the striking circadian and circannual periodicity of this disorder.

The hypothalamic activation triggers the trigeminovascular system. Nociceptive signals travel through the ophthalmic division of the trigeminal nerve (V1), producing the intense periorbital and temporal pain. This trigeminal activation simultaneously engages the trigeminal-autonomic reflex arc, a brainstem pathway connecting the trigeminal nucleus caudalis to the superior salivatory nucleus. Efferent parasympathetic fibers then travel via the greater petrosal nerve and the sphenopalatine ganglion to the lacrimal gland, nasal mucosa, and conjunctival vessels. This reflex arc is responsible for the ipsilateral autonomic features: lacrimation, conjunctival injection, nasal congestion, and rhinorrhea.

The associated miosis and ptosis (a partial Horner syndrome) result from sympathetic dysfunction, likely from compression or inflammation of the pericarotid sympathetic plexus within the cavernous sinus during the intense vasodilation and edema that accompany an attack. Unlike a complete Horner syndrome (which also includes anhidrosis of the entire face), cluster headache produces only a partial Horner syndrome because the sympathetic disruption occurs distal to the bifurcation of sudomotor fibers. This partial Horner syndrome can persist between attacks in long-standing cases.

A critical behavioral feature that directly follows from the intensity of hypothalamic and trigeminovascular activation is psychomotor agitation. Unlike migraine patients, who prefer to lie still in a dark room, cluster headache patients cannot remain still. They pace, rock, or even bang their heads. This restlessness is one of the most reliable clinical discriminators and is believed to result from the extreme severity of pain combined with autonomic arousal.

The reason alcohol reliably triggers attacks only during a cluster period (and not during remission) is thought to relate to hypothalamic sensitization. During an active cluster bout, the hypothalamic pacemaker is in a vulnerable, hyperexcitable state, and vasodilatory substances like alcohol lower the threshold for attack initiation.

2. Classification and Clinical Manifestation

Classification

Type	Definition	Key Feature
Episodic Cluster Headache	Cluster periods lasting 7 days to 1 year, separated by pain-free remission periods lasting at least 3 months	Accounts for approximately 80% to 90% of cases
Chronic Cluster Headache	Attacks occurring for more than 1 year without remission, or with remission periods lasting less than 3 months	About 10% to 20% of cases; may evolve from episodic form or arise de novo

Clinical Manifestation by Phase

Phase	Manifestation
Prodromal (Cluster Period Onset)	Vague unease, mild discomfort in the future attack site; not always present
Attack Phase (Individual Episode)	Explosive onset of severe unilateral orbital, supraorbital, or temporal pain reaching peak intensity within minutes; duration 15 to 180 minutes; frequency ranges from once every other day to 8 attacks per day
Autonomic Features (Ipsilateral)	Conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid edema, forehead and facial sweating, miosis, ptosis, sense of restlessness or agitation
Circadian Pattern	Attacks occur at predictable times, often 1 to 2 hours after falling asleep (linked to the first REM sleep period), earning the name "alarm clock headache"
Circannual Pattern	Cluster periods often recur during the same season each year, frequently spring or autumn, possibly related to changes in daylight hours and hypothalamic regulation
Remission Phase	Complete freedom from attacks; in episodic type, remission lasts at least 3 months

ICHD-3 Diagnostic Criteria Summary

Criterion	Requirement
A	At least 5 attacks fulfilling criteria B through D
B	Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes when untreated
C	Either or both: (1) at least one ipsilateral autonomic symptom (conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead/facial sweating, miosis, ptosis, eyelid edema), or (2) a sense of restlessness or agitation
D	Attack frequency between one every other day and 8 per day during a cluster period
E	Not better accounted for by another diagnosis

3. Diagnostic Workup

Test	Role	Key Findings
Clinical history and exam	Best initial and primary diagnostic method	Unilateral periorbital pain + ipsilateral autonomic features + restlessness + circadian pattern
MRI brain with contrast	Rule out secondary causes (required at least once)	Normal in primary cluster headache; used to exclude pituitary lesion, cavernous sinus pathology, posterior fossa lesion
MRA or CTA	If clinical suspicion for vascular pathology	Rule out carotid dissection, aneurysm, or AVM
ESR / CRP	If age > 50 or atypical features	Rule out giant cell arteritis
Indomethacin trial	Differentiates from other TACs if diagnosis is uncertain	Cluster headache does NOT respond to indomethacin (unlike hemicrania continua and paroxysmal hemicrania, which do)

Cluster headache is fundamentally a clinical diagnosis. There is no laboratory test, imaging finding, or biomarker that confirms it. The diagnosis rests entirely on pattern recognition: the combination of strictly unilateral severe pain in the V1 distribution, ipsilateral cranial autonomic symptoms, attack duration of 15 to 180 minutes, and the behavioral hallmark of agitation.

The role of MRI brain with gadolinium contrast is not to confirm cluster headache but to exclude dangerous mimics, particularly lesions in the pituitary region, cavernous sinus, or posterior fossa that can produce a secondary cluster-like phenotype (so-called "symptomatic cluster headache"). Current guidelines recommend that every patient with a new diagnosis of cluster headache undergo at least one brain MRI. If the MRI is normal, it does not need to be repeated for each cluster period.

Vascular imaging (MRA or CTA of the head and neck) is warranted when the presentation includes features atypical for cluster headache, such as a persistent neurological deficit, neck pain, or a new Horner syndrome outside of an attack, which may suggest carotid artery dissection.

An indomethacin trial is a functional diagnostic test used when there is uncertainty between cluster headache and other trigeminal autonomic cephalalgias. A dramatic and complete response to indomethacin is diagnostic of paroxysmal hemicrania or hemicrania continua. Cluster headache does not respond to indomethacin. This distinction is a high-yield exam point.

If the patient is over 50 years old, ESR and CRP should be obtained to exclude giant cell arteritis, which can present with severe unilateral head pain and may occasionally mimic cluster headache.

4. Management and Treatment

Setting	Intervention	Details
Acute Abortive (First-line)	High-flow 100% oxygen	12 to 15 L/min via non-rebreather mask for 15 to 20 minutes; effective in approximately 70% of attacks
Acute Abortive (First-line)	Sumatriptan subcutaneous injection	6 mg SC; onset of relief within 5 to 15 minutes; fastest pharmacologic abortive
Acute Abortive (Alternative)	Sumatriptan nasal spray or zolmitriptan nasal spray	Sumatriptan 20 mg intranasal or zolmitriptan 5 mg intranasal; slower onset than SC but useful when injection is not feasible
Transitional Prevention	Oral corticosteroids (prednisone)	Prednisone 60 to 80 mg/day for 5 days, then taper over 2 to 3 weeks; provides rapid suppression while maintenance preventive agent is titrated
Transitional Prevention	Greater occipital nerve (GON) block	Ipsilateral injection of local anesthetic (with or without corticosteroid); used as bridge therapy
Maintenance Prevention (First-line)	Verapamil	Start at 240 mg/day in divided doses, titrate up to 480 to 960 mg/day as tolerated; requires ECG monitoring before and after each dose increase due to risk of heart block
Maintenance Prevention (Second-line)	Lithium	600 to 1200 mg/day; requires monitoring of serum lithium levels, renal function, and thyroid function; mainly for chronic cluster headache
Maintenance Prevention (Others)	Topiramate, melatonin, galcanezumab (anti-CGRP monoclonal antibody)	Various levels of evidence; galcanezumab 300 mg SC monthly has shown efficacy in episodic cluster headache
Refractory Cases	Sphenopalatine ganglion stimulation, occipital nerve stimulation, deep brain stimulation	Considered only after failure of multiple pharmacologic strategies

Acute treatment focuses on speed. Because cluster attacks are short (15 to 180 minutes) and excruciating, slow-onset medications like oral analgesics are ineffective. The two first-line acute treatments are high-flow 100% oxygen and subcutaneous sumatriptan. Oxygen is administered at 12 to 15 L/min via a non-rebreather mask with a reservoir bag. The patient should be seated and leaning slightly forward. It is safe, has no significant contraindications, and can be repeated without limit. Subcutaneous sumatriptan at 6 mg acts within minutes and is the most rapidly effective pharmacologic agent. These two treatments can be used together. Oral triptans are generally too slow for cluster headache and are not recommended as first-line. Intranasal sumatriptan (20 mg) or intranasal zolmitriptan (5 mg) are alternatives with intermediate onset.

Opioids and barbiturate-containing analgesics have no role in cluster headache management. This is a commonly tested point. NSAIDs and acetaminophen are also ineffective for acute cluster attacks.

Transitional (bridge) prevention is initiated at the start of a cluster period to suppress attacks quickly while a slower-acting maintenance preventive is being titrated. Prednisone is the most commonly used transitional agent, started at 60 to 80 mg/day and tapered over 2 to 3 weeks. Corticosteroids should not be used long-term due to cumulative adverse effects. A greater occipital nerve block with local anesthetic (such as lidocaine or bupivacaine with or without methylprednisolone) on the ipsilateral side can also provide rapid, short-term relief.

Maintenance prevention is the cornerstone of long-term cluster management during a cluster period. Verapamil is the first-line maintenance preventive. It is started at 240 mg/day in two or three divided doses and titrated upward in increments of 80 mg every 1 to 2 weeks. Doses up to 960 mg/day may be necessary for refractory cases. Because verapamil at higher doses carries a risk of PR interval prolongation and heart block, an ECG must be performed at baseline and repeated after each dose increase. This ECG monitoring requirement is a frequently tested detail.

Lithium is an alternative, particularly in chronic cluster headache. It requires monitoring of serum lithium levels (target 0.6 to 1.0 mEq/L), thyroid function, and renal function. Lithium has a narrow therapeutic window, and toxicity can be precipitated by dehydration, NSAIDs, ACE inhibitors, and thiazide diuretics.

A notable contraindication: triptans and ergotamines should not be used within 24 hours of each other due to the risk of coronary vasospasm. Additionally, triptans are contraindicated in patients with uncontrolled hypertension, coronary artery disease, or a history of stroke.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Migraine	Unilateral headache, can be severe, may have autonomic features (lacrimation, nasal congestion can occur in migraine too)	Migraine lasts 4 to 72 hours (much longer); patient prefers to lie still in a dark, quiet room (photophobia, phonophobia); aura may be present; no strict circadian pattern
Paroxysmal Hemicrania	Unilateral headache with ipsilateral autonomic features; same TAC family	Paroxysmal hemicrania has shorter attacks (2 to 30 minutes), higher frequency (>5/day typically), and shows a complete response to indomethacin (absolute diagnostic criterion)
SUNCT / SUNA	Unilateral periorbital pain with autonomic features	Attacks are much shorter (1 to 600 seconds), frequency is very high (up to 200/day), and conjunctival injection with tearing is predominant; does not respond to oxygen or sumatriptan
Hemicrania Continua	Continuous unilateral headache with autonomic features	Pain is continuous (not episodic) with fluctuations; absolutely responsive to indomethacin
Trigeminal Neuralgia	Severe unilateral facial pain, brief attacks	Pain is in V2/V3 distribution (not V1/periorbital); triggered by light touch, chewing, or talking; no autonomic features; electric shock-like quality
Giant Cell (Temporal) Arteritis	Unilateral temporal headache, can be severe, in older patients	Age typically >50; associated with jaw claudication, visual symptoms, scalp tenderness; elevated ESR/CRP; temporal artery biopsy shows granulomatous inflammation
Carotid Artery Dissection	Unilateral head/face pain with ipsilateral Horner syndrome	Pain is usually constant (not episodic); may have neck pain; Horner syndrome is complete or associated with a bruit; confirmed with CTA/MRA
Acute Angle-Closure Glaucoma	Severe periorbital pain with red eye (conjunctival injection) and tearing	Eye is hard on palpation; pupil is mid-dilated and fixed (not miotic); corneal haziness; visual acuity decreased; intraocular pressure markedly elevated

6. Traps and High-Yield Pearls

The single most common trap on this topic is confusing cluster headache with migraine. Both cause severe unilateral headaches, and both can have autonomic features. The examiners rely on two reliable discriminators: (1) the patient's behavior during the attack, and (2) the duration of pain. A cluster headache patient is agitated and restless, unable to stay still, pacing the room. A migraine patient wants to lie in a dark, quiet room without moving. If the vignette describes a patient pacing or rocking during the headache, think cluster headache. If the patient is lying down with the lights off, think migraine. Attack duration is the second anchor: 15 to 180 minutes points to cluster; 4 to 72 hours points to migraine.

The second major trap involves differentiating among the trigeminal autonomic cephalalgias. The examiners distinguish these conditions primarily by attack duration and indomethacin responsiveness. Cluster headache attacks last 15 to 180 minutes and do not respond to indomethacin. Paroxysmal hemicrania attacks last 2 to 30 minutes and respond completely to indomethacin. Hemicrania continua is continuous rather than episodic and also responds completely to indomethacin. If a vignette describes a patient with a cluster-like headache that resolves completely with indomethacin, the answer is paroxysmal hemicrania, not cluster headache.

A third common error involves acute treatment selection. Students may select oral sumatriptan or oral analgesics for an acute cluster attack. This is incorrect. The speed of onset matters: cluster attacks are brief and intense, so treatment must work within minutes. The correct first-line agents are high-flow oxygen (12 to 15 L/min) and subcutaneous sumatriptan (6 mg). Oral formulations are too slow.

Finally, do not forget the ECG monitoring requirement with verapamil. If a question asks about the next step after starting or increasing verapamil, the answer is to obtain an ECG to evaluate for PR prolongation or heart block. This is a test of your knowledge of drug monitoring, not headache pathophysiology, and it appears with regularity.

The core competency being tested across all cluster headache questions is pattern recognition of a distinctive clinical syndrome: a young male smoker with episodic, strictly unilateral periorbital pain lasting under 3 hours, accompanied by ipsilateral tearing and nasal congestion, who is agitated and restless during the attack. Recognizing this pattern instantly is what the examiners expect.

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