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Trigeminal autonomic cephalalgias

Trigeminal autonomic cephalalgias (TACs) are a group of rare primary headache disorders characterized by strictly unilateral, severe pain in the distribution of the trigeminal nerve, accompanied by prominent ipsilateral cranial autonomic symptoms such as lacrimation, conjunctival injection, nasal congestion, rhinorrhea, eyelid edema, forehead sweating, and ptosis.^[1] These headaches are distinguished by their short duration, high frequency of attacks, and association with the trigeminovascular system and autonomic reflex activation, often showing circadian or circannual patterns in some subtypes.^[2] The TACs encompass four main subtypes according to the International Classification of Headache Disorders, third edition (ICHD-3): cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or with cranial autonomic symptoms (SUNA), and hemicrania continua.^[1] Cluster headache, the most common TAC with a prevalence of approximately 0.1%, features excruciating unilateral orbital, supraorbital, or temporal pain lasting 15–180 minutes, occurring 1–8 times per day during cluster periods that may last weeks to months, often with patient restlessness or agitation during attacks.^[2] Paroxysmal hemicrania involves shorter attacks of 2–30 minutes occurring more than five times daily (up to 40 times), with absolute responsiveness to indomethacin as a diagnostic hallmark.^[1] SUNCT and SUNA are marked by even briefer, stabbing pains lasting 1–600 seconds, triggered by innocuous stimuli and occurring up to hundreds of times per day, primarily affecting the first division of the trigeminal nerve and often refractory to treatment.^[2] Hemicrania continua, while continuous rather than paroxysmal, presents as a persistent unilateral headache of moderate intensity with exacerbations resembling other TACs, also showing complete response to indomethacin and autonomic features during flares.^[1] Across all TACs, neuroimaging such as MRI with gadolinium is recommended to rule out secondary causes like pituitary lesions, and the disorders disproportionately affect males for cluster headache but show varied gender distributions in others.^[2] Pathophysiologically, TACs involve central activation of the trigeminal-autonomic reflex pathway, with evidence of hypothalamic involvement—such as ipsilateral activation in cluster headache—contributing to the periodicity and autonomic manifestations.^[1] Management varies by subtype: acute treatments include high-flow oxygen and triptans for cluster headache, while indomethacin is first-line for paroxysmal hemicrania and hemicrania continua; SUNCT/SUNA often requires antiepileptics like lamotrigine, though many cases remain challenging.^[2] Early diagnosis is crucial, as delays of 3–6 years are common, particularly for cluster headache, underscoring the need for awareness among clinicians.^[1]

Overview

Definition

Trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral head pain in the trigeminal nerve distribution, accompanied by prominent ipsilateral cranial autonomic symptoms such as lacrimation, nasal congestion, conjunctival injection, rhinorrhea, eyelid edema, forehead or facial sweating, miosis, or ptosis.^[3] These attacks typically manifest as severe, short-lasting pain localized to the orbital, supraorbital, or temporal regions, occurring with high frequency and often involving agitation or restlessness during episodes.^[3] The underlying mechanism involves activation of the trigeminovascular system coupled with a trigeminal-parasympathetic reflex, leading to the autonomic features, while cranial sympathetic dysfunction appears secondary.^[3] The term "trigeminal autonomic cephalalgias" was first coined in 1997 by Goadsby and Lipton to unify a set of syndromes sharing trigeminovascular activation and prominent autonomic manifestations, previously recognized as distinct entities like cluster headache and paroxysmal hemicrania. This nomenclature was formally adopted in the second edition of the International Classification of Headache Disorders (ICHD-2) in 2004, initially encompassing three headache types, and expanded in subsequent revisions to reflect evolving clinical and pathophysiological understanding.^[1] The classification has been refined through editions of the ICHD, with the third edition (ICHD-3) in 2018 incorporating evidence from field testing to emphasize phenotypic, temporal, and therapeutic response criteria.^[3] TACs are distinguished from other primary headaches, such as migraine or tension-type headache, by their strictly unilateral pain, extreme severity, brief attack durations (ranging from seconds to hours depending on subtype), and predominance of autonomic activation over nausea or vomiting.^[3] Unlike migraines, which often last 4–72 hours and feature photophobia or phonophobia as dominant associated symptoms, TAC attacks emphasize ipsilateral parasympathetic features driven by trigeminal reflex pathways, with high frequency contributing to their debilitating impact.^[1] This shared profile underscores TACs as a cohesive category within primary headaches, separate from secondary causes or other trigeminal disorders.^[3]

Classification

Trigeminal autonomic cephalalgias (TACs) are classified into five primary disorders based on the International Classification of Headache Disorders, third edition (ICHD-3), which emphasizes differences in attack duration, frequency, associated autonomic features, and therapeutic responses.^[4] These include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and hemicrania continua.^[5] Each subtype shares unilateral trigeminal-distribution pain accompanied by ipsilateral cranial autonomic symptoms but is distinguished by specific temporal patterns and diagnostic hallmarks.^[6] Cluster headache, the most common TAC, is divided into episodic and chronic forms. Episodic cluster headache involves at least five attacks of severe, unilateral pain in the orbital, supraorbital, or temporal region lasting 15-180 minutes untreated, occurring from every other day up to eight times daily, with ipsilateral autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, or restlessness; attacks occur in bouts lasting 7 days to 1 year separated by pain-free remissions of at least 3 months.^[5] Chronic cluster headache follows the same attack criteria but lacks remissions or has them lasting less than 3 months for over 1 year.^[5] Paroxysmal hemicrania also has episodic and chronic variants, characterized by at least 20 attacks of severe unilateral orbital, supraorbital, or temporal pain lasting 2-30 minutes, with a frequency of at least five per day for more than half the time, accompanied by ipsilateral autonomic symptoms.^[7] A defining feature is the absolute response to indomethacin, typically at doses of 25-300 mg daily.^[7] Episodic paroxysmal hemicrania occurs in bouts with pain-free remissions lasting at least 3 months, while the chronic form persists for more than 1 year without such remissions or with intervals shorter than 3 months.^[5] Short-lasting unilateral neuralgiform headache attacks encompass SUNCT and SUNA, both featuring at least 20 attacks of moderate to severe unilateral orbital, supraorbital, temporal, or maxillary pain with neuralgiform features, lasting 1-600 seconds, and occurring with variable high frequency often exceeding dozens per day.^[8] SUNCT requires both conjunctival injection and lacrimation ipsilaterally during attacks, while SUNA involves at least one other cranial autonomic symptom (such as eyelid edema, forehead sweating, or nasal congestion) but neither or only one of conjunctival injection or tearing.^[9]^[10] Both can present in episodic forms with bouts lasting 7 days to 1 year separated by 3-month remissions or chronically without such intervals.^[5] Hemicrania continua is a continuous unilateral headache of moderate intensity present for more than 3 months, with exacerbations of severe pain and ipsilateral autonomic symptoms such as conjunctival injection or lacrimation, distinguishing it from other persistent headaches.^[11] It exhibits an absolute response to indomethacin, serving as a key diagnostic hallmark.^[11] Despite its non-paroxysmal nature, hemicrania continua is included in the TAC group due to its unilateral pain distribution and prominent ipsilateral cranial autonomic features during exacerbations, aligning it mechanistically with the paroxysmal TACs.^[6] It may occur in remitting (with periods of complete remission lasting at least 24 hours after 1 year) or unremitting subtypes.^[5]

Signs and Symptoms

Pain Characteristics

Trigeminal autonomic cephalalgias (TACs) are defined by attacks of severe, strictly unilateral pain localized to the distribution of the trigeminal nerve, most commonly affecting the orbital, supraorbital, or temporal regions, though involvement of the maxillary or mandibular branches can occur.^[12]^[1] The pain is typically excruciating in intensity, often described by patients as boring, burning, stabbing, throbbing, or electric shock-like, and it rapidly reaches peak severity within minutes before sustaining at a high level throughout the attack.^[12]^[13] In cluster headache, for instance, the pain is frequently rated as one of the most intense experiences known, surpassing that of renal colic or labor.^[1] Duration and frequency vary markedly across TAC subtypes: short-lasting neuralgiform headaches such as SUNCT and SUNA feature attacks lasting seconds to minutes (typically 5–240 seconds) with high frequency (up to hundreds per day), while cluster headache involves episodes of 15–180 minutes occurring 1–8 times daily, and hemicrania continua presents as continuous unilateral pain with exacerbations lasting minutes to days.^[12]^[1]^[13] Paroxysmal hemicrania attacks generally endure 2–30 minutes and occur more than five times per day.^[12]^[13] During attacks, patients often exhibit marked agitation or restlessness, such as pacing, rocking, or applying pressure to the affected area, in contrast to the stillness preferred in migraine.^[12]^[1] This behavioral response is particularly prominent in cluster headache, where up to 90% of patients report such motor activity.^[12] Cluster headache demonstrates notable circadian and circannual periodicity, with attacks often clustering at specific times of day (nocturnal predominance in many cases) and recurring seasonally in bouts lasting weeks to months, whereas other TACs like paroxysmal hemicrania and SUNCT show less predictable or daytime-dominant patterns.^[12]^[1] These pain episodes are accompanied by ipsilateral cranial autonomic symptoms, though the sensory pain profile remains the defining feature.^[1]

Autonomic Symptoms

Trigeminal autonomic cephalalgias (TACs) are distinguished by prominent ipsilateral cranial autonomic symptoms that accompany headache attacks, resulting from activation of the trigeminal-autonomic reflex.^[12] These symptoms are triggered during pain episodes and occur on the same side as the headache, underscoring their lateralized nature.^[14] The major autonomic features include conjunctival injection, lacrimation (tearing), nasal congestion, rhinorrhea, eyelid edema, and forehead or supraorbital sweating.^[12]^[14] These manifestations are highly prevalent, appearing in nearly all attacks across TAC subtypes, and contribute significantly to the clinical recognition of the disorders.^[12] Less common minor symptoms encompass ptosis, miosis, and aural fullness, which may present as part of an incomplete Horner's syndrome.^[14] These features, while not as consistently observed as the major ones, further support the autonomic involvement in TACs.^[12] The prominence of autonomic symptoms varies by subtype: they are most marked in cluster headache and paroxysmal hemicrania, where multiple features often co-occur per attack, whereas in short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), conjunctival injection and lacrimation predominate, with nasal symptoms being less frequent.^[14] In hemicrania continua, autonomic signs are typically milder during exacerbations but remain diagnostically essential.^[12] Their absence in some cases may complicate diagnosis, yet their ipsilateral presence is a core criterion for TAC classification.^[14]

Pathophysiology

Underlying Mechanisms

Trigeminal autonomic cephalalgias (TACs) are driven by activation of the trigeminovascular system, where sensory afferents from the trigeminal ganglion innervate cranial blood vessels and release neuropeptides that promote neurogenic inflammation and central pain signaling.^[2] This activation results in the release of calcitonin gene-related peptide (CGRP) from trigeminal nociceptive fibers (primarily C-fibers and Aδ-fibers), causing vasodilation of dural and cerebral vessels, plasma protein extravasation, and sensitization of second-order neurons in the trigeminal cervical complex.^[15] Levels of CGRP in external jugular vein blood rise significantly during TAC attacks, correlating with pain intensity and supporting its role in pain generation.^[16] Vasoactive intestinal peptide (VIP) is also elevated during episodes, contributing to further vasodilation and neurogenic inflammation, though its levels may more closely reflect parasympathetic activation than direct pain mechanisms.^[16] A key feature of TAC pathophysiology is the trigeminal-autonomic reflex, which links trigeminal pain pathways to ipsilateral cranial parasympathetic outflow.^[17] Afferent signals from activated trigeminal nociceptors converge in the trigeminal nucleus caudalis and project to the superior salivatory nucleus in the brainstem, triggering efferent parasympathetic fibers that synapse in the sphenopalatine ganglion.^[18] This reflex arc leads to release of parasympathetic mediators like VIP and acetylcholine, resulting in autonomic features such as lacrimation, nasal congestion, and eyelid edema, which are ipsilateral to the pain and proportional to its severity.^[17] Hypothalamic involvement plays a prominent role, particularly in cluster headache, the most common TAC, where functional imaging reveals activation of the posterior hypothalamus during spontaneous and nitroglycerin-induced attacks.^[19] Positron emission tomography (PET) studies show increased regional cerebral blood flow in this region specifically during bouts, suggesting it orchestrates attack timing through circadian and circannual rhythm dysregulation, as evidenced by the predictable daily and seasonal patterns of cluster periods.^[20] Genetic factors contribute modestly, with familial clustering observed in approximately 5-10% of cluster headache cases, indicating a polygenic inheritance pattern influenced by environmental interactions.^[21] Common triggers, including alcohol, nitroglycerin, and histamine, provoke attacks by inducing vasodilation and activating the trigeminovascular system in susceptible individuals, often within minutes of exposure.^[22] Most TACs are idiopathic, lacking identifiable structural lesions, though secondary forms can arise from underlying pathologies such as pituitary tumors, which may compress adjacent neural structures and mimic primary TAC symptoms.^[23]

Anatomical Basis

Trigeminal autonomic cephalalgias (TACs) involve activation of the trigeminovascular system, where first-order sensory neurons originate in the trigeminal ganglion and transmit nociceptive signals primarily through the ophthalmic division (V1) of the trigeminal nerve to the brainstem. These pseudounipolar neurons detect painful stimuli from dural and extracranial vascular structures, projecting centrally via thinly myelinated Aδ and unmyelinated C fibers that synapse in the trigeminal subnucleus caudalis.^[24] This pathway forms the primary conduit for the unilateral, severe pain characteristic of TACs, with the ophthalmic division predominating due to its innervation of periorbital and temporal regions.^[12] In the brainstem, the trigeminal cervical complex (TCC)—comprising the trigeminal subnucleus caudalis and upper cervical dorsal horn (C1-C2)—serves as a critical integration site for trigeminal and cervical nociceptive inputs, facilitating convergence that amplifies head and neck pain signals. Neurons within the TCC receive convergent afferents from the trigeminal ganglion and upper cervical roots, enabling the processing and relay of pain to higher thalamic and cortical centers while interfacing with autonomic regulatory nuclei.^[24] This complex underscores the anatomical overlap between trigeminal pain processing and autonomic modulation in TACs.^[12] The posterior hypothalamus acts as a key supratentorial integrator in TACs, exhibiting activation during attacks and structural abnormalities such as gray matter alterations, with direct descending projections to the trigeminal nucleus caudalis influencing periodicity and attack initiation. These connections, including histaminergic and orexinergic pathways, link circadian rhythms to trigeminal nociception, as evidenced by functional imaging studies showing ipsilateral hypothalamic hypermetabolism.^[20]^[24] Autonomic manifestations in TACs arise from parasympathetic outflow originating in the superior salivatory nucleus, which projects via the greater petrosal nerve to the pterygopalatine (sphenopalatine) ganglion, releasing acetylcholine and vasoactive intestinal peptide to innervate lacrimal and nasal glands. This pathway, activated reflexively by trigeminal input, accounts for ipsilateral symptoms like conjunctival injection and rhinorrhea, with the ganglion serving as a peripheral relay for cranial parasympathetic effects.^[12] Sympathetic hypofunction, involving the superior cervical ganglion, contributes to features such as ptosis and miosis through impaired oculosympathetic tone.^[24] Vascular involvement in TACs centers on neurogenic dilation of dural meningeal vessels and extracranial arteries, innervated by trigeminal afferents that release calcitonin gene-related peptide (CGRP) upon activation, promoting sterile inflammation and pain sensitization. This dilation, particularly of the middle meningeal artery and external carotid branches, correlates with attack intensity and is modulated by the TCC and hypothalamic inputs.^[24]^[2]

Diagnosis

Diagnostic Criteria

Trigeminal autonomic cephalalgias (TACs) are diagnosed using the standardized criteria outlined in the International Classification of Headache Disorders, third edition (ICHD-3), which requires the fulfillment of specific attack characteristics including unilateral pain in the trigeminal distribution and associated ipsilateral cranial autonomic symptoms or restlessness.^[25] These criteria emphasize the necessity of multiple documented attacks to establish the diagnosis, with the exact number, duration, and frequency tailored to each subtype to distinguish TACs from other headache disorders.^[25] For all primary TACs, the headache must not be better accounted for by another ICHD-3 diagnosis, ensuring exclusion of secondary causes through clinical evaluation and, when indicated, neuroimaging.^[25] The general framework for primary TACs involves at least five to twenty attacks of severe or very severe unilateral pain, lasting from seconds to hours depending on the subtype, accompanied by at least one ipsilateral autonomic symptom such as conjunctival injection, lacrimation, nasal congestion, or ptosis, or a sense of restlessness.^[25] Type-specific criteria further refine this: for cluster headache (3.1), attacks last 15-180 minutes with a frequency of every other day to eight per day during bouts lasting 7 days to 1 year, separated by pain-free remissions of at least 3 months in episodic cases.^[25] Paroxysmal hemicrania (3.2) requires at least 20 attacks lasting 2-30 minutes, occurring five or more times per day, and complete prevention by therapeutic doses of indomethacin.^[25] Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT, 3.3.1) necessitate at least 20 attacks of moderate to severe pain lasting 1-600 seconds in the trigeminal distribution, with both conjunctival injection and lacrimation as autonomic features, occurring at least once daily for more than half the time and often exceeding 50 attacks per day.^[25] Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA, 3.3.2) follows similar parameters but requires only one autonomic symptom, such as conjunctival injection or lacrimation, rather than both.^[25] Hemicrania continua (3.4) is characterized by continuous unilateral headache present for more than 3 months, with fluctuating pain and exacerbations accompanied by autonomic symptoms or agitation, also completely responsive to indomethacin.^[25] Secondary TACs (3.5) are diagnosed when headache features resemble a primary TAC but are attributable to an underlying disorder, such as a tumor, vascular malformation, or infection, fulfilling criteria that include evidence of causation demonstrated by temporal relation to the onset or progression of the causative condition, parallel worsening or improvement with it, or characteristic features of the underlying disorder.^[25] Neuroimaging, such as MRI, is recommended to rule out secondary causes like tumors when atypical features are present, including onset after age 40, progressive symptoms, or associated neurological signs.^[25] The ICHD-3, published in 2018, updated the criteria for TACs by formally including SUNA as a distinct entity alongside SUNCT to account for variations in autonomic symptom prominence, and refined the description of hemicrania continua to emphasize its continuous nature with exacerbations.^[25]

Differential Diagnosis

Trigeminal autonomic cephalalgias (TACs) must be differentiated from other primary headaches and secondary mimics to ensure accurate diagnosis, as per the International Classification of Headache Disorders, third edition (ICHD-3).^[25] Primary mimics include migraine, which features longer attack durations (typically 4-72 hours), pulsating pain often accompanied by nausea and vomiting, and sensory sensitivities such as photophobia and phonophobia, whereas TACs involve shorter, strictly unilateral attacks (15 minutes to 3 hours for cluster headache) with prominent ipsilateral cranial autonomic symptoms like lacrimation or nasal congestion, and patient restlessness during attacks.^[26]^[27] Another key mimic is trigeminal neuralgia, characterized by brief (seconds to 2 minutes), shock-like or stabbing pain in the trigeminal distribution (often V2/V3 branches), triggered by touch or chewing, without autonomic features or the higher attack frequency seen in TACs like short-lasting unilateral neuralgiform headache attacks (SUNCT).^[28]^[29] Secondary causes that can present with TAC-like symptoms include structural lesions such as pituitary adenomas (e.g., prolactinomas or meningiomas, accounting for about 32.5% of secondary cluster headache cases), vascular malformations like aneurysms or arteriovenous malformations (37.7% of cases), and inflammatory conditions such as sinusitis or sphenoid sinus mucocele (27.3% of cases).^[27] Red flags suggesting secondary etiology include sudden onset, progressive worsening of pain, atypical features beyond unilateral trigeminal distribution (e.g., bilateral involvement or radiation to the neck), or associated neurological deficits such as focal weakness or papilledema.^[29]^[26] Distinguishing clinical features aid in separation from mimics; for instance, TACs often show agitation or restlessness during attacks, contrasting with the preference for stillness in migraine, and include autonomic signs like conjunctival injection or eyelid edema in over 90% of cases.^[28]^[27] A unique response to indomethacin, providing complete relief in paroxysmal hemicrania and hemicrania continua but not in cluster headache or mimics, further supports TAC diagnosis in responsive subtypes.^[26]^[28] Diagnostic evaluation typically involves neuroimaging with contrast-enhanced MRI of the brain (including the sella turcica) for all suspected TACs, particularly if onset is sudden, features are atypical, or red flags are present, to exclude secondary causes; routine laboratory tests are not indicated unless systemic illness is suspected.^[27]^[26] Rare overlaps may occur, such as TACs presenting with aura-like features resembling hemiplegic migraine, though the presence of autonomic symptoms and shorter duration favor TACs.^[25]

Management

Acute Treatment

The acute treatment of trigeminal autonomic cephalalgias (TACs) focuses on rapidly aborting individual attacks to provide immediate relief, with strategies tailored primarily to cluster headache as the prototype disorder, though adaptations exist for rarer subtypes like paroxysmal hemicrania, SUNCT, and SUNA. Established interventions target the intense, short-duration pain and autonomic features without addressing underlying attack frequency. Oxygen therapy is a first-line option for cluster headache, involving inhalation of 100% oxygen at 12-15 L/min via a non-rebreather mask for 15-20 minutes, which achieves substantial or complete pain relief in 70-78% of attacks within 15 minutes.^[30]^[31] This non-pharmacologic approach is FDA-approved and recommended by guidelines, though it requires access to equipment and may be less practical for patients with mobility limitations or comorbidities like severe chronic obstructive pulmonary disease.^[31] Triptans, particularly sumatriptan, are highly effective for acute cluster headache relief. Subcutaneous sumatriptan at a 6 mg dose provides headache relief in approximately 75-96% of attacks within 15 minutes, making it suitable for the rapid onset of symptoms.^[32]^[33] For shorter-lasting attacks in subtypes like SUNCT, intranasal sumatriptan (20 mg) or zolmitriptan (5-10 mg) may be used, though efficacy is lower, with response in only about 7% of SUNCT cases based on limited data.^[33]^[34] Triptans are contraindicated in patients with cardiovascular disease due to vasoconstrictive effects and are limited to a maximum of 12 mg subcutaneously per 24 hours to minimize side effects like chest tightness or nausea.^[35] Non-invasive vagus nerve stimulation (nVNS) using the gammaCore device offers an alternative for acute attack abortion in cluster headache and paroxysmal hemicrania. In cluster headache, two-minute stimulations at pain onset yield response rates of 34-48% compared to sham, superior to placebo in randomized trials.^[36]^[37] For paroxysmal hemicrania, nVNS has demonstrated reductions in attack severity and frequency by 50-75% in case series, providing a non-pharmacologic option when indomethacin tolerance is an issue.^[38] Evidence for nVNS is emerging, with FDA approval for episodic cluster headache, though long-term response may wane.^[36] In SUNCT and SUNA, intravenous or subcutaneous lidocaine serves as the primary acute intervention during active phases, achieving response rates of 80-94% in case reports, often administered at 1-3.5 mg/kg over several days for refractory attacks.^[39] Triptans and oxygen show minimal benefit in these subtypes, with sumatriptan aborting attacks in fewer than 10% of cases.^[34] Overall limitations include subtype-specific inefficacy—such as triptans in SUNCT—and contraindications like vascular risks for triptans or equipment needs for oxygen. Opioids are avoided in acute TAC management due to lack of efficacy, risk of dependency, and potential for rebound headaches.^[40] Evidence levels are high for oxygen and sumatriptan in cluster headache based on randomized controlled trials, moderate for nVNS from sham-controlled studies, and lower (case series) for lidocaine in SUNCT/SUNA.^[31]^[32]^[36]

Preventive Treatment

Preventive treatment for trigeminal autonomic cephalalgias (TACs) aims to reduce the frequency, duration, and severity of headache attacks, with strategies tailored to the specific TAC subtype due to varying pathophysiology and responses. Pharmacological options are prioritized based on evidence from clinical trials and guidelines, while non-pharmacological interventions are reserved for refractory cases or transitional support. The indomethacin response serves as a key diagnostic feature for indomethacin-responsive TACs like paroxysmal hemicrania and hemicrania continua.^[41] For cluster headache, the most common TAC, verapamil is the first-line preventive agent, typically dosed at 480-960 mg per day in divided doses, with gradual titration starting from 240 mg to assess efficacy and tolerability.^[42] Electrocardiogram (ECG) monitoring is essential before initiation and with each dose increase to detect cardiac conduction abnormalities, such as PR interval prolongation. In refractory cluster headache, topiramate (starting at 25 mg daily, titrated to 100-400 mg per day) or lithium (800-900 mg per day in divided doses) may be considered as alternatives, though evidence is primarily from open-label studies showing moderate attack reduction. Paroxysmal hemicrania and hemicrania continua require indomethacin as the cornerstone of prevention, with doses ranging from 25-300 mg per day in divided administrations, often achieving complete remission in responsive patients.^[41] This absolute response underscores its diagnostic utility.^[43] Gastrointestinal protection with proton pump inhibitors is recommended due to risks of peptic ulcers and bleeding, alongside baseline renal function assessment to avoid exacerbation in vulnerable patients.^[41] For short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and autonomic symptoms (SUNA), lamotrigine is the first-line preventive treatment, typically started at 25 mg daily and titrated to 100-400 mg per day.^[44] Alternatives include oxcarbazepine (600-1800 mg/day), topiramate (50-200 mg/day), or gabapentin (up to 3600 mg/day) if lamotrigine is ineffective or not tolerated, based on case series and open-label studies showing response rates of 50-80%.^[44]^[45] Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) represent a targeted option for episodic cluster headache prevention; galcanezumab (300 mg subcutaneous monthly, administered as three 100 mg injections) was FDA-approved in 2019 based on phase 3 trials with 71% of patients achieving at least a 50% reduction in weekly attack frequency compared to 53% with placebo.^[46]^[47] Non-pharmacological approaches include greater occipital nerve blocks using a combination of local anesthetic (e.g., lidocaine) and corticosteroids, which provide transitional relief by reducing attack frequency for weeks to months in cluster headache patients.^[48] For intractable chronic cluster headache unresponsive to medical therapy, hypothalamic deep brain stimulation offers long-term pain relief in over 60% of cases, with electrodes implanted in the posterior hypothalamus to modulate attack-generating circuits, as evidenced by follow-up studies showing sustained efficacy without major complications.^[49] Transitional therapies bridge the gap during preventive regimen initiation or cluster bout escalation; short-term oral corticosteroids (e.g., prednisone 50-80 mg daily, tapered over 10-12 days) or greater occipital nerve blocks are employed to rapidly suppress attacks while awaiting pharmacotherapy effects. Overall, treatment selection requires individualized assessment, with close monitoring for adverse effects like verapamil-induced bradycardia or indomethacin-related gastrointestinal toxicity to optimize outcomes.^[41]

Epidemiology and Prognosis

Epidemiology

Trigeminal autonomic cephalalgias (TACs) are a group of rare primary headache disorders with an overall global prevalence of less than 1% of the population.^[24] Among the TACs, cluster headache is the most common, with a lifetime prevalence of approximately 0.1% (range 0.03%–0.2%), though recent estimates suggest a 5-year prevalence of approximately 56.7 per 100,000 individuals.^[50]^[51] The other TAC subtypes are considerably rarer, with paroxysmal hemicrania having a 1-year prevalence of approximately 1–2 per 100,000, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or with cranial autonomic symptoms (SUNA) at approximately 6.6 per 100,000, and hemicrania continua at about 1 in 100,000 to 2.2 per 100,000 for 1-year prevalence.^[52]^[53]^[54] Demographic patterns vary across TAC subtypes. Cluster headache exhibits a strong male predominance, with a male-to-female ratio of 3:1 to 6:1, and typically has a peak onset age between 20 and 40 years.^[55] In contrast, paroxysmal hemicrania shows a more balanced sex distribution (approximately 1:1 ratio) and a later mean onset around 40 years, while hemicrania continua has a slight female predominance (1.6:1), and SUNCT/SUNA a mild male bias (1.5:1).^[56]^[57]^[58] Geographic variations indicate higher prevalence rates of TACs, particularly cluster headache, in Western populations compared to other regions; for instance, lifetime prevalence estimates are around 87 per 100,000 in Georgia and 41.4 per 100,000 in Brazil, lower than typical Western figures.^[59] Genetic factors play a role, with familial aggregation observed in 5% to 20% of cluster headache cases, often following an autosomal dominant pattern with reduced penetrance, and associations noted with certain HLA alleles.^[60]^[61] Risk factors are most clearly established for cluster headache, where smoking significantly increases susceptibility and attack frequency, and alcohol consumption acts as a potent trigger during bouts, affecting 50% to 80% of patients.^[62]^[63] For the other TACs, no strong environmental or lifestyle risk factors have been consistently identified.^[24]

Prognosis

Trigeminal autonomic cephalalgias (TACs) exhibit variable natural histories depending on the specific subtype, with most patients experiencing a mix of remission and recurrence over time. In cluster headache, the most common TAC, approximately 80-90% of cases begin as the episodic form, characterized by cluster periods lasting weeks to months separated by remission phases of months to years.^[64] About 10-15% of patients present with the chronic form from onset, and among those starting episodic, 10-15% may convert to chronic over time, though transitions in the reverse direction also occur at lower rates of around 6%.^[65] Remission becomes more common after age 50-60, often with prolonged pain-free intervals.^[66] Subtype-specific trajectories differ markedly. Paroxysmal hemicrania frequently remits spontaneously, with episodic forms showing remission periods of months to years and even chronic cases occasionally achieving long-lasting resolution without intervention.^[67] Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) tends to be more persistent, with attacks continuing for decades in some patients, though the brief duration (seconds to minutes) results in relatively lower overall severity compared to longer-lasting TACs.^[53] Hemicrania continua is typically chronic and lifelong, persisting without significant remission, but remains manageable with targeted therapy.^[68] The impact on quality of life is profound, particularly in chronic cluster headache, where the excruciating intensity drives a high risk of suicidality; studies report suicidal ideation in up to 55% of patients during active bouts.^[69] While treatments can substantially reduce attack frequency and severity, they rarely achieve full cure, leaving many patients with ongoing episodic or chronic burden.^[50] Key prognostic factors include smoking, which is associated with increased risk of progression to chronicity in cluster headache, and earlier age of onset, which correlates with higher likelihood of refractory or chronic courses in some cohorts.^[70] In indomethacin-responsive TACs like paroxysmal hemicrania and hemicrania continua, a positive response to the drug predicts effective long-term control and improved outcomes.^[41] Longitudinally, attacks in cluster headache often decrease in frequency and severity with advancing age, accompanied by extended remissions, though spontaneous full remission remains rare.^[50]

References

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Overview of Trigeminal Autonomic Cephalalgias - PMC - NIH
The term trigeminal autonomic cephalalgias (TACs) encompasses four primary headache disorders – cluster headache, paroxysmal hemicrania (PH), hemicrania ...
[2]
Trigeminal autonomic cephalgias - PMC - NIH
Trigeminal autonomic cephalgias (TACs) are primary headaches with a common clinical phenotype consisting of trigeminal pain with autonomic signs.
[3]
[PDF] International Classification of Headache Disorders, 3rd edition
Trigeminal autonomic cephalalgias in ICHD-3 on the basis that the pain is typically unilateral, as are the cranial autonomic symptoms when present. (in ICHD ...
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3. Trigeminal autonomic cephalalgias (TACs)
No readable text found in the HTML.<|separator|>
[5]
[PDF] The International Classification of Headache Disorders
Trigeminal autonomic cephalalgias. 3.1. Cluster headache. 3.1.1. Episodic ... Not better accounted for by another ICHD-3 diagnosis. 4.7 Primary stabbing headache.
[6]
Classification of Trigeminal Autonomic Cephalalgia - PubMed
The TAC group includes cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks (SUNHAs) and their 2 subforms.
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3.2 Paroxysmal hemicrania - ICHD-3
Feb 6, 2018 · Diagnostic criteria: At least 20 attacks fulfilling criteria B-E; Severe unilateral orbital, supraorbital and/or temporal pain lasting 2-30 ...
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3.3 Short-lasting unilateral neuralgiform headache attacks - ICHD-3
Nov 1, 2018 · Attacks of moderate or severe, strictly unilateral head pain lasting seconds to minutes, occurring at least once a day and usually associated with prominent ...<|control11|><|separator|>
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3.3.1 Short-lasting unilateral neuralgiform headache ... - ICHD-3
Jan 30, 2018 · Diagnostic criteria: Attacks fulfilling criteria for 3.3 Short-lasting unilateral neuralgiform headache attacks, and criterion B below; Both ...
[10]
3.3.2 Short-lasting unilateral neuralgiform headache attacks with ...
3.3.2 Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). A. Attacks fulfilling criteria for 3.3 ...
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3.4 Hemicrania continua - ICHD-3
Feb 6, 2018 · Diagnostic criteria: Unilateral headache fulfilling criteria B-D; Present for >3 months, with exacerbations of moderate or greater intensity ...
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The pain is excruciatingly severe. It is located mainly around the orbital and temporal regions, although any part of the head can be affected. The headache ...
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Trigeminal autonomic cephalalgias (TACs) are primary headache disorders characterized by unilateral head pain occurring in association with ipsilateral cranial ...
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The Neuropharmacology of Cluster Headache and other Trigeminal ...
The trigeminal autonomic cephalalgias (TACs) are a group of primary headaches characterised by unilateral pain associated with ipsilateral cranial autonomic ...
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Trigeminovascular System - an overview | ScienceDirect Topics
Due to the trigeminovascular system activation, CGRP is released from trigeminal nociceptive afferents (Aδ-fibers and C-fibers) resulting in vasodilation ...
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Medline ® Abstract for Reference 5 of 'Pathophysiology of the ...
During the attacks external jugular vein blood levels of CGRP and VIP were raised while there was no change in neuropeptide Y or substance P. Calcitonin gene- ...
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A translational in vivo model of trigeminal autonomic cephalalgias
Oct 11, 2012 · Activation of the trigeminovascular system by stimulation of dural structures also causes neuronal activation in the superior salivatory ...<|separator|>
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Neuroanatomy, Pterygopalatine Ganglion - StatPearls - NCBI - NIH
Jul 24, 2023 · [28] A proposed mechanism for the TACs occurs through a trigeminal autonomic reflex, in which afferent signals from the dura mater and cranial ...
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Hypothalamic activation in cluster headache attacks - ScienceDirect
Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache.
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Hypothalamic activation in cluster headache attacks - PubMed
Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache.
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Family History of Cluster Headache: A Systematic Review - PMC
Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family.
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Hallmarks of primary headache: part 3 – cluster headache
Oct 2, 2025 · Alcohol consumption has been identified as a significant trigger reported by up to 50–80% of patients with CH, with a slightly higher rate (65%) ...<|separator|>
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Secondary (Symptomatic) Trigeminal Autonomic Cephalalgia - PMC
... pituitary tumor in a case of TACs does not necessarily point toward causality. ... Intracranial tumors are probably the most common causes for secondary TACs ...
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Cluster Headache - StatPearls - NCBI Bookshelf
Cluster headaches are unilateral periocular headaches occurring between 15 minutes to 3 hours, with episodes usually occurring twice a day for weeks to months ...<|control11|><|separator|>
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[PDF] International Classification of Headache Disorders, 3rd edition
Trigeminal autonomic cephalalgias in ICHD-3 on the basis that the pain is typically unilateral, as are the cranial autonomic symptoms when present. (in ICHD ...
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Pearls & Oy-sters: Trigeminal autonomic cephalalgias - Neurology.org
Mar 15, 2010 · The trigeminal autonomic cephalalgias (TACs) are a group of primary headaches that are characterized by unilaterality of pain, a relatively short duration of ...
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Cluster headache: an update on clinical features, epidemiology ...
Mar 8, 2024 · TACs are primary headache disorders characterized by pain localized in the first division of the trigeminal nerve in parallel with ipsilateral ...
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Cluster Headache and Other Trigeminal Autonomic Cephalalgias
Purpose of review: This article covers the clinical features, differential diagnosis, and management of the trigeminal autonomic cephalalgias (TACs).
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Oct 23, 2007 · TACs include episodic and chronic cluster headache, episodic and chronic paroxysmal hemicrania, SUNCT, and hypnic headache. If the duration is ...
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[PDF] TRIGEMINAL AUTONOMIC CEPHALGIAS - NCBI
Opiates, non-steroidal anti-inflammatory drugs and combina- tion analgesics generally have no role in the acute manage- ment of CH in most patients.Missing: opioids avoidance<|control11|><|separator|>
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Chronic Paroxysmal Hemicrania - StatPearls - NCBI Bookshelf - NIH
Chronic paroxysmal hemicrania (CPH) is a severely debilitating unilateral headache. The complications mostly arise from the treatment of CPH with indomethacin ...Introduction · Evaluation · Treatment / Management · Toxicity and Adverse Effect...
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Verapamil for Cluster Headache. Clinical Pharmacology and ...
Jan 5, 2009 · The dose of verapamil needed in the preventive treatment of cluster headache patients varies considerably. Thus, doses from 240 mg to 960 mg are ...Abstract · COMPARISON OF DOSES OF... · CLINICAL USE OF...
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Therapeutical approaches to paroxysmal hemicrania, hemicrania ...
Jul 20, 2017 · Indomethacin is the best treatment both for HC and PH. For the acute treatment of HC, piroxicam and celecoxib have shown good results, whilst ...
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[PDF] Emgality - accessdata.fda.gov
The pharmacokinetics of galcanezumab-gnlm were not affected by age, sex, race, subtypes of migraine spectrum (episodic or chronic migraine), or headache ...
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Jun 4, 2019, Approval FDA Approves Emgality (galcanezumab-gnlm) for the Treatment of Episodic Cluster Headache. Sep 27, 2018, Approval FDA Approves Emgality ...
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Acute Treatment of Cluster Headache with Great Occipital Nerve ...
This case shows that GON blockade may be an alternative treatment as an acute and short-term preventative therapy in CH patients.
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Positron emission tomography and functional MRI studies have demonstrated that the ipsilateral posterior hypothalamus is activated during cluster headache ...
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Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 ...
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Prevalence, demographics, comorbidities, and treatment patterns of ...
Jul 21, 2025 · Five-year prevalence of cluster headache was highest (56.7 per 100,000), followed by paroxysmal hemicrania (22.0 per 100,000), hemicrania ...
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Epidemiology and clinical features of paroxysmal hemicrania
Jan 11, 2024 · The relative frequency of paroxysmal hemicrania was estimated to be 0.3% (95% CI, 0.2%-0.5%) among adult patients evaluated for headache in ...
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There are three categories of treatment for trigeminal autonomic cephalalgia, including SUNCT and SUNA: acute, preventive, and bridge therapies. Short Term ...
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Paroxysmal hemicrania - Orphanet
Paroxysmal hemicrania (PH) prevalence is unknown. There is a male-to-female ratio of 1:1. The mean age of onset is 40 years (range 3-81 years).
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Hemicrania Continua - an overview | ScienceDirect Topics
HC is a rare disorder that may have a prevalence of up to 1% of the population. HC is more common in females than males, 1.6:1.
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SUNCT syndrome - Orphanet
The prevalence is estimated at approximately 1 in 15,000. It is slightly more predominant in males (male-to-female ratio of 1.5:1), with a mean age of onset ...
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Epidemiology, burden and clinical spectrum of cluster headache
Sep 20, 2023 · The first epidemiological data from Georgia and Brazil estimated the lifetime prevalence of CH to be 87 per 100,000 (15) and 41.4 per 100,000 ( ...
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Prevalence of familial cluster headache: a systematic review and ...
Apr 25, 2020 · The population rate of familial cluster headache (CH) has been reported to be as high as 20% however this varies considerably across studies.Missing: clustering | Show results with:clustering
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Epidemiology and genetics of cluster headache - The Lancet
Cluster headache, the most severe primary headache, is characterised by unilateral pain, ipsilateral autonomic features, and, in many cases, restlessness.Missing: clustering | Show results with:clustering
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Smoking and cluster headache presentation and responsiveness to ...
Sep 17, 2024 · Smoking is significantly correlated with the daily frequency of CH attacks, the frequency of CH bouts in the past five years, and the HIT-6 scores among our ...Missing: TACs | Show results with:TACs
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Alcohol and Cluster Headaches - Evans - 2009 - Wiley Online Library
Jan 5, 2009 · Alcohol is a well-known potent trigger for CH attacks, first described by Horton in 1941. It elicits attacks in about 50-80% of patients, less ...Missing: TACs | Show results with:TACs<|control11|><|separator|>
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Headache disorders: differentiating and managing the common ...
Cluster headache is episodic in 80–90% of cases, with attacks occurring daily for a few weeks to a few months, followed by a gap of a few months to a few years.
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3.1 Cluster headache - ICHD-3
Feb 6, 2018 · About 10-15% of patients have 3.1.2 Chronic cluster headache, without such remission periods. In a large series with good follow-up, one quarter ...3.1.1 Episodic cluster headache · 3.1.2 Chronic cluster headacheMissing: conversion rates
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Exploration of Prolonged Remission and the Natural Course of ... - NIH
Jun 13, 2025 · This cohort offers rare insight into prolonged CH remission, typically starting around the mid-50s after 25 years of active disease.
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a case report. Long-lasting remission in the chronic stage - PubMed
The remission could be a spontaneous one or it could in some way be related to the protracted indomethacin treatment; the authors favour the former possibility.Missing: prognosis | Show results with:prognosis
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Hemicrania Continua - StatPearls - NCBI Bookshelf - NIH
Jul 27, 2024 · [3] Other trigeminal autonomic cephalalgias include cluster headache ... The ICHD-3 diagnostic criteria for hemicrania continua focus on 3 ...
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Cluster headache attack carries a high suicidality compared to the interictal or between-bouts state. An intensive treatment to reduce cluster headache ...
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A New Look at Tobacco Use and Headaches | NeurologyLive
Aug 3, 2018 · ... smoking could be a risk factor for worsening of cluster headache from an episodic to a chronic condition. However, further study is needed ...Missing: prognostic chronicity