Cluster headache …

Peter J Goadsby MD PhD FRS

Headache & Pain

Updated 02.27.2024
Released 02.14.1994
Expires For CME 02.27.2027

Cluster headache

Author: Peter J Goadsby MD PhD FRS

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Editor: Shuu-Jiun Wang MD

Cluster headache

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Introduction

Overview

Cluster headache is a primary headache disorder characterized by severe, unilateral pain that is orbital, supraorbital, or temporal and 15 minutes to 3 hours in duration occurring one to eight times a day. Accompanying symptoms include ipsilateral: conjunctival injection, lacrimation, nasal congestion, aural fullness, rhinorrhea, facial sweating, eyelid edema, and miosis. The current update provides the latest understanding and management of this disorder, including the latest clinical trial data.

Key points

	• Cluster headache is a relatively common, very severe form of primary headache that belongs to the family of trigeminal autonomic cephalalgias.
	• Cluster headache involves dysfunction of central nervous system elements concerned with pain control and with links to circadian and circannual mechanisms.
	• Acute cluster headache can be treated with oxygen, intranasal triptans (sumatriptan and zolmitriptan), and injected sumatriptan, and for episodic cluster headache noninvasive vagal nerve stimulation.
	• Medicines or strategies useful in the preventive management of cluster headache include verapamil, lithium, corticosteroids, topiramate, melatonin, greater occipital nerve injection, the calcitonin gene-related peptide (CGRP) monoclonal antibody galcanezumab for episodic cluster headache, and noninvasive vagal nerve stimulation.
	• Sphenopalatine ganglion stimulation has been demonstrated to be useful for the treatment of medically refractory chronic cluster headache.

Historical note and terminology

Cluster headache has been recognized for over 350 years (184); an excellent clinical description can be found in Van Swieten’s textbook (170) and a reasonable description in the Spanish literature (295). It has been known by many names, notably Horton headache in North America (168; 166; 167) and migrainous neuralgia in the United Kingdom (155; 26; 196; 30). Other names that have probably described substantially similar syndromes, perhaps now called the trigeminal autonomic cephalalgias (197), include ciliary neuralgia (323), erythroprosopalgia of Bing (27), and hemicrania periodic neuralgiforms (291). Symonds recognized it as a particular variety of headache (377). Sphenopalatine ganglion neurosis (364) and Vidian neuralgia (388) were described as affecting females and were probably migraine with a facial distribution and cranial autonomic symptoms, given data that confirm the common appearance of cranial autonomic features in migraine (178). The periodicity of the attacks led to the current nomenclature (156; 157; 158), cluster headache (192), which seems to describe it well and respect its biology.

Clinical manifestations

Presentation and course

There are two major forms of cluster headache, namely, episodic cluster headache and chronic cluster headache (158). The term “attack” is generally used to refer to a distinct episode of pain, whereas a bout or period is a series or “cluster” of attacks. Thus, episodic cluster headache is characterized by periods lasting 7 days to 1 year separated by remission periods lasting 3 months or longer. Chronic cluster headache is characterized by the absence of remission for 1 year or short remissions of less than 3 months. It should be noted that the time for remissions has increased from 1 month in ICHD-2 to three months in ICHD-3. Both classifications assume no preventive treatments. Patients’ cluster headaches may evolve from the episodic to the chronic form with sporadic, late-onset attacks, a high frequency of cluster periods, and short-lived duration of remission periods when the headache is still the episodic form, all correlating with the transition to the chronic form (385). Of patients with episodic cluster headache, 14.4% transition to the chronic form; of patients with the chronic form, 6.3% transition to the episodic form (370). Chronic cluster headache may be seen de novo (primary), or it may evolve from the episodic form (secondary); differences between the two include earlier cluster headache onset and duration of attacks varying more frequently between 120 and 180 minutes (384), although in practice this distinction seems to have no clinical utility (80). Cluster headache is extremely disabling when patients are experiencing a bout (64). Even with chronic cluster headache, cycling can occur (169), which could be called “micro-cycling”; a similar phenomenon is seen in SUNCT (169). Somewhat more than half of patients report that they can predict the onset of their bout, including when they note what are described as “shadows” (297).

The attack consists of the rapid onset of headache that builds to a peak in about 10 to 15 minutes and lasts for approximately 30 to 180 minutes, although longer attacks are not infrequent (392). The headache is almost always unilateral. In order of decreasing frequency, common sites of pain are orbital, retro-orbital, temporal, supraorbital, and infraorbital. The head pain occasionally switches sides, and in extremely rare cases it can be bilateral. The pain is described as the worst experienced by humans (35). Typically, the pain is in the trigeminal nerve distribution, although extra-trigeminal pain, especially in the suboccipital area, is well recognized. Rarely, attacks may occur without cranial autonomic symptoms, although in each such case we have seen, the patients have had typical agitation and restlessness. Cranial autonomic symptoms can also occur alone (237), typically in patients who have been treated with nerve root sections (132). The number of attacks per day varies, usually from one to three, but the International Headache Society classification allows from one every second day to eight per day. Generally, attacks occurred more often in chronic than in episodic cluster headache for those participating in trials (175). More frequent or treatment-resistant attacks should lead to consideration of other trigeminal-autonomic syndromes, such as paroxysmal hemicrania. Migrainous features can be seen in cluster headache, such as nausea, photophobia, and phonophobia, in as many as half of cases (16; 413; 367; 117). Moreover, between 6% (354; 66) and 14% (17) of patients report typical migraine aura with their cluster headache. It is likely related to associated migraine (301). Hemiplegic aura has been reported (359) as has prolonged aura (198). This needs careful evaluation from a diagnostic viewpoint. Cluster headache is well-recognized in children (256; 195; 226), and this author has seen a 3-year-old child with a convincing story, although it may begin as late as 89 years of age (108). About one third of patients report improvement of cluster headache attacks with sexual activity (151). The recognized male preponderance probably contributes to misdiagnosis in females (225; 367; 117). Females are reported to have longer bouts and are more likely to have chronic cluster headache (115) or longer attacks (Liaw at al 2022). Authors have noted premonitory symptoms, such as dull ache or cranial autonomic symptoms, before an attack (366; 48). Similarly, about one third of patients with episodic cluster headache can predict the onset of their bout, most usually by pain (49), which many refer to as a “shadow.”

One remarkable aspect of cluster headache is its periodicity, with attacks often occurring at almost the same time every day (86; 201); this phenomenon has resulted in suggestions that human circadian pacemaker physiology is involved (20). Nocturnal attacks have been reported to occur during both REM and non-REM sleep periods (191). Sleep studies show reduced REM sleep in cluster headache (19). The timing of attacks with regard to sleep stage is an unresolved issue (145). Attacks are characterized by excruciating pain that is regarded by sufferers, without exception, as the worst pain that they have ever experienced. The pain is associated with ipsilateral cranial parasympathetic overactivity, lacrimation, conjunctival injection and nasal stuffiness or rhinorrhea, and an ipsilateral partial (third neuron) Horner syndrome (82; 83) with ptosis and miosis. These symptoms are equally likely in episodic and chronic cluster headache (120). In exceptional cases, the cranial autonomic symptoms can result in obvious swelling (12) or even nose bleeds. Voice change, which is likely a cranial autonomic symptom, may be seen in cluster headache (355; 178). Although less common than in migraine, photophobia and phonophobia occur in cluster headache (395) and when present are more often lateralized to the side of the pain (169; 31).

Neurologic examination may reveal mild ptosis and miosis on the side of the headache, especially during or immediately following the attack, and impaired trigeminal sensation from time to time, although the latter will trigger a search for a lesion. Ipsilateral tenderness of the carotid artery, periorbital swelling, and congestion of the conjunctiva are also noted. During a bout, a subtle but convincing, mild, partial Horner syndrome ipsilateral to the pain is often present. Alcohol, nitroglycerin, and histamine can induce attacks during cluster periods (168; 85). Nitroglycerin-induced attacks have the same phenotype as spontaneous attacks and allow dissection of disease features, such as pre-pain onset of cranial autonomic symptoms (403). Allodynia and interictal pain are seen in cluster headache (197; 236; 409) and, when present, the patient almost invariably has a personal or family history of migraine.

Triggering of bouts of cluster headache has been reported with COVID-19 vaccination (32; 46); whether this is happenstance or a real association requires further investigation.

Prognosis and complications

The prognosis of episodic cluster headache is generally good. As patients age, cluster headaches usually disappear. Approximately 10% of patients have the chronic variety of cluster headache, which tends to run a difficult and often intractable course. Transformation from the episodic to the chronic form, and less commonly from the chronic to the episodic variety, is well recognized. In a follow-up study with a range of 2 to 17 years, 27% of 60 newly diagnosed patients had only one attack over a mean follow-up of 8.9 years (363). A number of patients with cluster headache have obstructive sleep apnea (191; 47; 285; 286; 147), and it can be clinically useful to inquire about such symptoms and investigate appropriately.

Clinical vignette

A 42-year-old male presented with a 13-year history of strictly left-sided headache. The pain centered on the eye and felt as though the eye was being pulled out with sharp prongs. Attacks of pain lasted 90 minutes and were associated with left-sided photophobia and a sense of restlessness. He had left-sided lacrimation and a sense of aural fullness. The attacks came in bouts for 9 weeks every 18 months to 2 years, and he was pain-free between times. He had a normal general and neurologic examination.

Biological basis

Etiology and pathogenesis

The etiology of cluster headaches is not known. It seems likely that some inherited basis for the problem exists (334; 333; 264; 265; 213; 376; 332; 402), although it has proved hard to study (94). Genome-wide association approaches have identified loci (importantly, not causal variants, including other loci not overlapping), with some previously reported in migraine, and some overlap between European and Han Chinese populations (154; 289; 45). Cluster headache is probably not related to the familial hemiplegic migraine CACNA1A gene (150; 361) or to nitric oxide synthase genes (362), or to methylenetetrahydrofolate reductase C>T polymorphism (346). There are reports of a polymorphism in the hypocretin receptor 2 gene (313; 312; 345), which would be attractive because of the localization in the hypothalamus (365), although the finding could not be reproduced by others (22; 296), and the CSF levels of hypocretin-1 are unaltered in cluster headache (42). Functional variants of CYP3A4 are not associated with response to verapamil (304).

The three major aspects of the pathophysiology of cluster headache are the trigeminal distribution of the pain, the autonomic features, and, more important, the inherent periodicity of the attacks and bouts (132). Ekbom’s observation of a patient suffering an acute cluster headache demonstrating angiographic changes in the internal carotid artery suggested a pathological focus in the region of the cavernous sinus (86). The arguments for this locus for the disease have been set out clearly (271; 153). There are no consistent markers of inflammation when measured in the periphery (318; 369), signs of cavernous sinus inflammation when studied with SPECT/MRI (343), and no vessel wall inflammation on MRI (258). Three lines of evidence suggest that the cavernous sinus is not the site of the basic biological problem. The clinical manifestations outlined above, in particular the periodicity, the neuroendocrine changes, and the functional neuroimaging results (55; 65), suggest that cluster headache involves biological dysfunction in the posterior hypothalamic grey matter pacemaker neurons.

Trigeminal autonomic activation in cluster headache. The pain of cluster headache is a first division of trigeminal phenomenon. Many of the autonomic features are due to seventh nerve activation, whereas the remaining changes are due to a transient cervical sympathetic deficiency. It is both clinically likely and experimentally clear (138) that a trigeminal-autonomic reflex underlies the pain expression of cluster headache. There are neuropeptide changes in the cranial circulation in both calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (130; 101), in tears (177) and nociception (96) release during headache that reflect the trigeminal and autonomic dimensions of the syndrome. Interestingly, CGRP can trigger attacks in patients with episodic cluster headache in a bout and not out of one (397), whereas CGRP levels are associated with disease activity (368). Interestingly, pituitary adenylate cyclase activating polypeptide (PACAP) triggers attacks at about the same rate as vasoactive intestinal peptide (398), without attendant release of CGRP (298) or vasoactive intestinal peptide (70). Similarly, levcromakalim can trigger cluster headache attacks when patients are in bout or have chronic cluster headache but not when patients with episodic cluster headache are between bouts (05).

Human studies have shown that retinal plasma extravasation does not seem to be active in cluster headache (253), suggesting it is irrelevant, at least as far as experimental plasma protein extravasation is concerned (272). Interestingly, in rats with 5-HT1D immunoreactivity there are documented primary afferents fibers that innervate postganglionic neurons in the sphenopalatine ganglion, suggesting a site for modulation by triptans (172). MRI-based measurements of sphenopalatine ganglion volume demonstrated that the ganglion is larger in patients and larger on the affected side (411). Taken together, the clinical and experimental evidence has suggested the term “trigeminal autonomic cephalalgias” as an umbrella term for cluster headache and related conditions (140). Drummond argues for a peripheral sympathetic autonomic disturbance (84), and minimal systemic autonomic disturbances are reported (394). For cluster headache, a crucial aspect of the dysfunction appears to lie within the ipsilateral hypothalamic grey (245; 106), and it is clear that the carotid flow changes are driven by the ophthalmic division of the trigeminal nerve and are not due to cluster headache as such. Further evidence of brain mechanisms in patients with cluster headache is the fact that the nociceptive flexion reflex threshold is asymmetrically reduced (337). More challenging is the observation of a typical cluster headache patient whose attacks persist after trigeminal root section (132; 174). In comparison to migraine, it is notable that there is no defect in habituation of the nociceptive blink reflex in cluster headache (165), with lateralized facilitation of central pain pathways (164). Although the site of action of sumatriptan has never been fully resolved, human (67) and animal (275) evidence continues to develop the concept of a possible central site of action.

Neuroendocrine changes in cluster headache. Kudrow pointed out that testosterone levels are altered in patients with cluster headache during a bout (187; 189). Leone and colleagues identified reduced responses to stimulation by thyrotropin-releasing hormone (212), and interesting observations have been made of disordered circadian rhythm for cortisol, growth hormone, luteinizing hormone, and prolactin (44; Waldenlind and Gustafsson 1987). Despite suggested involvement of the hypothalamic-pituitary axis, somatostatin infusion does not trigger acute cluster headache even with suppression of growth hormone (217). One area involved in human clock systems is the suprachiasmatic nucleus in the hypothalamic grey, which sits at the base of the third ventricle (267; 266). Melatonin is produced by the pineal gland and has a strong circadian rhythm, which is regulated by the suprachiasmatic nucleus. Connections between the retina and the hypothalamus are thought to provide light cues for the circadian rhythm (162). The characteristic nocturnal peak of melatonin secretion is blunted during the active phase of cluster headache (399), whereas urinary excretion of 6-sulphatoxymelatonin, the main metabolite of melatonin, is reduced both within and between bouts compared with controls (211). This suggests a defect with some permanent nature possibly amenable to treatment (204). Involvement in some part of nitric oxide mechanisms in cluster headache is supported by the finding of elevated levels of nitric oxide-oxidation end products in the CSF of patients with cluster headache (374). Latencies of the endogenous event-related-potential components are significantly increased during the cluster period as compared with outside the cluster period and with healthy subjects (99), further contributing to the notion of a central nervous system dysfunction.

Functional imaging and other physiological studies of cluster headache. Acute cluster headache triggered by nitroglycerin produces brain activations on positron emission tomography (PET) that fall into three categories: areas generally associated with pain, an area that seems specific to cluster headache, and vascular structures (245). The anterior cingulate was significantly activated, as would be expected, because in most human PET pain studies, activation of the anterior cingulate is observed, perhaps as a part of the affective response. Its degree of activation seems to track the subjective reporting of pain (248) and can be seen in spontaneous attacks (372) and when using fMRI (269). Activation was also noted in the frontal cortex and insulae and ventroposterior thalamus contralateral to the side of the pain. In addition, activation in the ipsilateral basal ganglia was observed. This is not the first observation of basal ganglia changes associated with pain (51; 72). This may simply relate to movement, the wish to move that is common in cluster patients, or even some deliberate inhibition of movement. Moreover, after occipital nerve stimulation (see Management section), there was normalization of pain matrix areas and lower pons but not of the posterior hypothalamic region. Remarkably, the perigenual anterior cingulate cortex was hyperactive in occipital nerve stimulation responders compared to nonresponders (228). It has been shown that pain responses to nasal ammonia are stronger in patients with cluster headache in the hypothalamus than in controls (344). The use of resting state connectivity analysis of abnormal patterns of hypothalamic connectivity with areas active in pain has been reported (311); this methodology will require more work. It may have a parallel in cortical hyperexcitability changes reported in episodic cluster headache (57).

The only activated area that is particular to cluster headache is a region near the base of the third ventricle, in the region of the posterior hypothalamic gray matter. One may speculate that orexinergic neurons play some role at this level (163), and indeed, data demonstrate reduced orexin levels in the CSF of patients with cluster headache (18). Activation of the hypothalamic gray matter in this region is not seen in migraine (02), nor in experimental first (ophthalmic) division of trigeminal nerve head pain (251). This region is not activated when the patient is out of a bout (246) but, remarkably, seems to have some structural difference when compared to control brains, notably a subtle increase in gray matter volume in the posterior hypothalamus (244). Moreover, a PET scan of a patient with both cluster headache and migraine who had a migraine at the time of the PET scan only showed brainstem, and not hypothalamic, activation (14). An increase of 20 Hz in the local field potential power in the region of the posterior hypothalamus has been noted in a patient undergoing implantation who had a spontaneous attack of cluster headache (33). These observations have led to implantation of deep brain stimulating electrodes into this portion of the brain with excellent outcomes in otherwise intractable patients (116; 209). Stimulation of the posterior hypothalamic region using the implanted electrodes produces a unique pattern of activation and de-activation in the brain, suggesting that the therapeutic effect is specific and not head pain generic (252). Similarly, 1H-MRS studies have reported reduced N-acetylaspartate levels, implying local neuronal loss or dysfunction in the posterior hypothalamic region (224; 400) whereas resting-state network fMRI demonstrated increased connectivity between hypothalamic and thalamic nuclei in cluster headache (321). Supporting a brain basis for cluster headache, 11C-diprenorphine PET studies reveal reduced pineal opioid receptor availability (373) and triggering of attacks from emotional trauma (336). It is to be expected that discussion remains as to both the mechanism and effective site of stimulation. It has been noted through indirect means that the optimal site for stimulation is located posterior to the hypothalamus (111; 287), although the definitive anatomical definition of the posterior hypothalamus in humans seems unclear if one considers the basis on which the structure has been defined. It has been shown using high-resolution T1-weighted MRI that cortical thickness in patients with cluster headache is reduced compared to controls, perhaps related to disease duration, ie, as a consequence not a cause (347), and has been refined to the middle cingulate, temporal, and lingual sulcal regions (71). The demonstration that peripheral provocation (149; 262) or activation of cranial autonomic symptoms do not trigger attacks of cluster headache reinforces the view of the condition as being driven from the central nervous system (131). Moreover, using a machine learning approach, it is possible to delineate the brains of patients with cluster headache from controls with 98% accuracy (259); some work will need to be done to make such approaches useful at an individual level.

Further supporting the central nervous system/pacemaker understanding of cluster headache is the circannual variation, with a peak during the Northern winter (20; 356).

During acute cluster headache, activation or signal on the PET studies is observed in the region of the cavernous sinus (245) and has been shown, using MRA, to be due to internal carotid artery vasodilation (247). The same region is activated during capsaicin-induced experimental head pain (246; 249), but when capsaicin is injected into the skin innervated by the mandibular division of the trigeminal nerve or the ipsilateral leg, no carotid dilation is observed (249). Moreover, after trigeminal root section, attacks of tearing without pain are well recognized (132; 223). These data imply that the activation of the carotid does not relate specifically to cluster headache, but that it is a trigeminovascular autonomic reflex to first division pain. The flow changes are, therefore, an epiphenomenon of the trigeminal activation, and not part of the disease generation process in cluster headache.

Differential diagnosis

The differential diagnosis for cluster headache lies between other trigeminal autonomic cephalalgia and the so-called secondary cluster headache syndromes, where pituitary tumor pathology is an important consideration (218; 219; 102; 103; 339; 180). Unfortunately, cluster headache is often missed (126), and many patients have unnecessary dental (300) and ENT procedures (13). Reasons for missing the diagnosis include gender (ie, a female patient) (13) and the presence of migrainous features, such as photophobia or phonophobia (391). The primary headaches that arise in the differential diagnosis of cluster headache include paroxysmal hemicrania, short-lasting neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and hemicrania continua (140; 352). These can be differentiated by clinical features, such as length and frequency of attacks, and by the response to indomethacin, which is absent for cluster headache, at least in an open-label study (10) and in the author’s placebo-controlled experience. It is likely that cases of cluster headache labeled as indomethacin-sensitive are misdiagnosed (308). Trigeminal neuralgia is sometimes mistaken for cluster headache, but the attacks are much shorter, and autonomic activation does not seem to be an important issue. Hypnic headache is a more moderate form of headache that is usually seen in the elderly. It is characterized by attacks of moderately severe headache that come on after falling asleep. The attacks can usually be controlled by lithium taken at night or by caffeine consumption (316; 282; 146; 77; 171; 268).

Table 1. Diagnostic Criteria for Cluster Headaches After ICHD-3

	At least five attacks fulfilling the following criteria:
		• Severe or very severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180 minutes if untreated.
		• Headache accompanied by one of the following:
			- ipsilateral conjunctival infection or lacrimation - ipsilateral nasal congestion or rhinorrhea - ipsilateral eyelid edema - ipsilateral forehead and facial sweating - ipsilateral forehead and facial flushing - ipsilateral miosis or ptosis, or - a sense of restlessness or agitation
		• Attacks have a frequency from one every other day to eight per day
		• Attacks are not attributed to another disorder
	Episodic cluster headaches also have at least two cluster periods lasting 7 days to 1 year and separated by pain-free remission periods of 3 months or more.
	Chronic cluster headaches also have attacks that recur for more than 1 year, without remission periods or with remission periods lasting less than 3 months.
(158)

It could be argued that secondary cluster headache should be divided into lesions that produce trigeminal-autonomic activation, which one might call pseudo-secondary cluster headache, where episodicity is not a key feature, and true secondary cluster headache. The latter is likely to be due to lesions in and around the diencephalon. A secondary cluster headache should be suspected when the clinical features of the headache are atypical. Atypical features include lack of periodicity, inter-attack pain (although this can be seen with frequent attacks), poor response to medications, and neurologic signs other than a partial Horner syndrome. Aural fullness has been removed as a cranial autonomic symptom being regarded as not adding to the classification; this author dissented from that view. Interestingly, diagnosis and management are considerable concerns to general practitioners and neurologists alike (40).

Table 2. Differential Diagnosis of Trigeminal Autonomic Cephalalgias

Other primary trigeminal autonomic cephalalgias
	• Paroxysmal hemicrania
	• SUNCT/SUNA (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features) syndrome

Confusing conditions

Table 3. Similar Conditions or Secondary Syndromes

Similar secondary headaches
	• Tolosa-Hunt syndrome • Maxillary sinusitis • Temporal arteritis • Raeder paratrigeminal neuralgia (133) • Trigeminal neuralgia
Secondary trigeminal autonomic cephalalgias – cluster-like headaches
	• Vascular:
		- Carotid artery dissection (325; 230; 317; 143; 387; 41) or aneurysm (148) - Vertebral artery dissection (60) or aneurysm (406) - Pseudoaneurysm of intracavernous carotid artery (185) - Anterior communicating artery aneurysm (148) - Occipital lobe AVM (231) - Middle cerebral artery territory AVM (274) - AVM in soft tissue of scalp above ear (382) - Frontal lobe and corpus callosum AVM (123) - Cervical cord infarction (69) - Lateral medullary infarction (52) - Frontotemporal subdural hematoma (114) - Trigeminal root compression (260)

	• Tumors:
		- Pituitary tumors (381; 148; 219; 279; 102; 103; 220; 339) - Hypothalamic tumors (389) - Parasellar meningioma (152) - Sphenoidal meningioma (203; 261) - Epidermoid tumor in the prepontine (behind the dorsum sella turcica) (221) - Clival epidermoid (238) - Tentorial meningioma (379) - High cervical meningioma (193) - Nasopharyngeal carcinoma (11) - C3 root fibrosis (59)

	• Infective:
		- Maxillary sinusitis (261) - Orbito-sphenoidal aspergillosis (159) - Herpes zoster ophthalmicus (335)
	• Posttraumatic or surgery:
		- Facial trauma (197) - Following enucleation of eye (322; 255; 310; 100) - Cataract surgery (128)

	• Dental:
		- Impacted wisdom tooth (324) - Following dental extraction (371)
	• Miscellaneous:
		- Cervical Syringomyelia and Chiari malformation (348) - Idiopathic intracranial hypertension (396)

Management

The management of cluster headache can be divided into the management of the acute attacks of pain and preventive management to reduce the number of attacks or control the attacks during a bout (134; 280; 161; 73; 250). Broadly, treatments and responses are comparable in Southeast Asia (202). Some surgical options are available, and these may afford a more permanent solution; however, they are not guaranteed to work, nor are they without significant morbidity. Medication overuse headache has now been reported in patients with cluster headache who all had migrainous biology (294); practitioners should be aware of this complication. The author has seen a similar problem with regular cannabis use, which is generally not helpful in cluster headache (215).

Preventive treatments. The options for preventive treatment in cluster headache are determined largely by the bout length not by the designation of episodic versus chronic cluster headache. Preventives may be regarded as short-term or long-term based on how quickly they act and how long they can be safely used. Most experts would now favor verapamil as the first-line preventive treatment, although for some patients with short bouts, limited courses of oral corticosteroids alone (173; 09), or in combination with verapamil (288), ergotamine (118), or methysergide (62) can be very useful strategies.

Verapamil has been recognized as a useful option for some time (119). It is superior to placebo (206) and compares favorably with lithium (39). What has clearly emerged from clinical practice is the need to use higher doses than had initially been considered and certainly higher than those used in cardiological indications. Although most patients will start on doses as low as 40 mg twice daily, doses up to 960 mg daily are now employed (290). Side effects, such as constipation and leg swelling can be a problem (351), but more difficult is the issue of cardiovascular safety. Verapamil can cause heart block by slowing conduction in the atrioventricular node (357), as demonstrated by prolongation of the A-H interval (278). Given that the PR interval on the ECG is made up of atrial conduction and A-H and His bundle conduction, it may be difficult to monitor subtle early effects as the verapamil dose is increased. This question needs study in this group of patients, but for the moment it seems appropriate to do a baseline ECG and then repeat the ECG 1 to 2 weeks after a dose change, usually in 80 mg increments, when doses exceed 240 mg daily (56; 199). We have also seen a malignant skin lesion related to verapamil usage, lymphomatoid papulosis (01), which may prove an issue in the future. Interestingly, the mechanism of action of verapamil in cluster headache has not yet been identified; an effect on the circadian clock is attractive (34).

Melatonin may be helpful as a cluster headache preventive (207; 302; 309; 125). Similarly, topiramate has proved effective in a number of cases (407; 113; 338; 194; 208; 314); a controlled trial is required.

Galcanezumab, a CGRP monoclonal antibody (24) useful in the preventive treatment of migraine (74), at 300 mg s/c, is superior to placebo in reducing attacks of cluster headache in patients with the episodic type (137). Interestingly, a patient global impression reporting “much better” experienced a median weekly reduction of attacks of 43% over the first 3 weeks, validating a 50% responder rate as patient centric (186). A randomized controlled trial of galcanezumab in the preventive treatment of chronic cluster headache reported out negative (76), whereas open-label use suggests there may be a cohort who responds (331; 257) and in whom it is well tolerated in the medium term (319); the latter is the author’s clinical impression. It is notable that clinical trials in cluster headache are difficult, with many pitfalls (75). It is well tolerated and offers a clear mechanism-based approach to therapy (43).

Because of its side effects, lithium carbonate is mainly used for the prophylactic treatment of chronic cluster headache, but it is sometimes employed in the episodic variety (87; 88; 188; 241). The usual dose of lithium is 600 to 900 mg per day in divided doses. Lithium levels should be obtained within the first week and periodically thereafter. The serum level required for therapeutic response is usually 0.4 to 0.8 mEq/L. Lithium and verapamil were shown to be similar in a comparative trial (39). The side effects of lithium are significant, and its use needs to be carefully monitored. Neurotoxic effects such as tremor, lethargy, slurred speech, blurred vision, confusion, nystagmus, ataxia, extrapyramidal signs, and seizures can occur if toxic levels are reached. Concomitant use of sodium-depleting diuretics should be avoided, as sodium depletion will result in high lithium levels and neurotoxicity. Long-term effects such as hypothyroidism and renal complications must be monitored when patients with chronic cluster headache use lithium for extended periods of time. Polymorphonuclear leukocytosis is a common reaction to lithium and is often mistaken for occult infection. Concomitant use with indomethacin can increase the lithium level; an important consideration is a trial in a relatively refractory patient in consideration of paroxysmal hemicrania.

An open study suggested that valproate is effective as a preventive treatment of cluster headache (160), but a subsequent controlled study showed no advantage (95). Melatonin may be helpful as a cluster headache preventive (207; 302; 309; 125). Intranasal capsaicin application has also been used (235), and intranasal civamide has modest effects (338). Induction of nitrate tolerance is not helpful in cluster headache (50). Gabapentin has been reported to be useful in cluster headache in some cases (04; 200; 380). Testosterone therapy has been used with some success for refractory cluster headache (375). Psilocybin (340), LSD use (349), and 2-bromo-lysergic acid diethylamide use (179) have been reported to be useful. The utility is not entirely surprising given psychedelics are serotonin 5-HT2 receptor agonists (254), as was methysergide. Each requires more controlled investigations. Given the involvement of circadian biology in cluster headache (23), the possible use of sodium oxybate as a preventive in chronic cluster headache is an interesting new suggestion (181).

Interestingly, circannual variation in newer triptans has been suggested to be helpful as preventives in cluster headache, although the studies have not been easy to conduct (273). As a short-term preventive approach, a course of intravenous dihydroergotamine can be helpful (276). Candasartan was not effective in a controlled trial (386).

Acute attack treatment. Cluster headache attacks often peak rapidly and, thus, require a treatment that has a quick onset. Moreover, the established placebo effect in cluster headache (284) makes it necessary to conduct controlled trials.

Many patients with acute cluster headache respond well to treatment with oxygen inhalation (190; 109). A placebo-controlled study has established clearly that oxygen is superior to air in the treatment of acute cluster headache (54). This should be given as 100% oxygen at 10 to 12 L/min for 15 minutes. It seems important to have a high flow and high oxygen content, whereas hyperbaric oxygen confers no prophylactic benefit above its treatment in acute attacks (283). Patients suggest, and there is some evidence for (303), ultra-high flow oxygen; this needs to be studied. Some proportion of patients who are treated with oxygen for acute attacks have the attacks rebound quickly when it is stopped (124), and this can limit the utility of oxygen therapy. Remarkably, when studied, high flow oxygen is not clearly helpful for migraine (358).

Injectable sumatriptan is an exceptionally useful treatment for patients with cluster headache (130). It is effective and rapid in onset (92), with no dose-response benefit over 6 mg and no evidence of tachyphylaxis (93), although there has been one report of increased headache frequency (327). In general, long-term use of injectable sumatriptan in chronic cluster headache, even on a daily basis, seems well tolerated and retains efficacy (205). Interestingly, only longer attacks and increased attack frequency, which have differential diagnostic implications, seem to predict the small (< 10%) nonresponder rate (127). Sumatriptan is not effective when given preemptively as 100 mg orally three times daily (263), although longer acting triptans, such as frovatriptan (122), have been used in open-label fashion. Both intranasal sumatriptan (20 mg) (390) and intranasal zolmitriptan (5 mg) (53; 315) have been shown to be effective in acute cluster headache in placebo-controlled trials. Olanzapine has been reported to be helpful for acute cluster headache (328); this requires a controlled trial.

Dihydroergotamine is effective in the relief of acute attacks of cluster headache (166). Intravenous administration gives rapid relief in less than 10 minutes, whereas intramuscular injection takes longer to be effective. Intranasal administration of dihydroergotamine may also be of benefit (07). Dihydroergotamine can be used repetitively to improve some patients with more difficult cluster headache (240). Clinical experience suggests that ergotamine by inhalation may be useful, although the oral and suppository formulations are too slow acting.

Locally applied lidocaine nasal drops have been reported to be effective in the treatment of acute attacks of cluster headache (183). Patients are told to lie supine with the head tilted backwards toward the floor at 30 degrees and turned to the side of the headache. A nasal dropper may be used and the dose (1 mL of 4% lidocaine) repeated once after 15 minutes. An interesting extension of this concept is the use of cocaine in cluster headache, which works for some patients (299), presumably in the same way as lidocaine (58).

Procedures. Injection of certain nerves and more radical procedures have been employed in patients with frequent or intractable attacks of cluster headache.

Injections of methylprednisolone (120 mg) with lidocaine into the greater occipital nerve ipsilateral to the site of attack have been reported to result in remissions lasting from 5 to 73 days (08). This is a simple, relatively benign procedure that seems to help some patients (06; 03; 216; 144). It has been suggested to be no better than oral steroids (405), a question that needs prospective study. Interestingly, changes in the nociception-specific blink reflex do not predict a clinical effect (38), suggesting that the mechanism is rostral in the CNS. Blockade of the sphenopalatine ganglion using cocaine or lidocaine is a useful temporary measure to give freedom from attacks for a few days, although an endoscopic study reported two of 21 patients having a break of 12 months or more (104; 307). The recurrence rate is high, however. In a series, 40% of patients with cluster headache reported improvement after radiofrequency lesion of the ipsilateral sphenopalatine ganglion (107; 277). Microvascular decompression does not seem useful (293).

Initial studies with noninvasive vagal nerve stimulation (nVNS) have been promising (281). It has been shown to be superior to standard of care for the prevention of attacks of cluster headache in an open-label study (121). Two randomized sham-controlled studies reported nVNS to be effective in the acute treatment of cluster headache in patients with the episodic type and not the chronic type (353; 131). Data from two randomized sham-controlled trials with sphenopalatine ganglion stimulation were positive (342; 141). This may evolve as the treatment of choice for medically refractory chronic cluster headache, as strong longer-term follow-up (176; 21) and cost effectiveness (306) data are now available.

Given the progress in neuromodulatory approaches, destructive procedures are, over time, becoming unacceptable.

A small number of patients with cluster headache are intractable to treatment and require consideration for surgical treatment (142). Accepted favorable indications for surgical treatment include (1) strictly unilateral headache, (2) total resistance to medical therapy or significant contraindications to the use of effective medical therapy, and (3) a stable personality profile without the potential for addictive behavior.

One destructive procedure is radiofrequency thermocoagulation of the trigeminal ganglion (292; 242). The procedure is essentially the same as that done for trigeminal neuralgia, except that both the first and second divisions of the trigeminal nerve are made fully analgesic. The overall results have been encouraging. Almost 75% of patients become free of cluster headache attacks. Recurrence of pain is possible, however, after a number of years. A repeat surgical procedure is considered in such patients. Corneal analgesia with resulting potential corneal infection or opacification and anesthesia dolorosa is an important sequela. The benefit from surgery generally outweighs the potential sequelae, and, therefore, it is worth considering in patients with total resistance to medical treatment. Injections of percutaneous retrogasserian glycerol rhizolysis have resulted in an initial 83% improvement with a 39% recurrence (305); numbers are small, and the uncontrolled nature of the injection is unattractive.

Gamma knife radiosurgery has been suggested (112), but an open study indicates that such an approach is not useful in the long term (81) and can produce deafferentation pain (79). A more invasive approach is trigeminal root section. There are two substantial series in the literature (182; 174), and morbidity is considerable.

Based on functional imaging studies that identified the posterior hypothalamic grey as a target area of importance in cluster headache (245), deep brain stimulation has been used. Early reports indicate that this approach is effective in some patients (116; 210; 209), although again caution is required because one death has been reported (341). An alternative is occipital nerve stimulation, which is widely regarded as being helpful (36; 37; 227) and is without significant morbidity or mortality. It has a good long-term effect (229) and is to be preferred over deep-brain stimulation procedures. A completed clinical comparing 30% or 100% of the paresthesia threshold showed no difference, although participants in both arms saw reductions in median attack frequency (408). Long-term observations of three years or more suggest persistence of benefit (214). Burst mode treatment may be as useful as tonic stimulation (110).

Other treatments. There has been discussion on the use of hallucinogenic drugs to treat cluster headache. Perhaps one quarter of patients have used such treatments (326). Much work needs to be done to understand whether such an approach has a sustainable role or whether it is a distraction (243) given the comparable pharmacology between, for example, BOL-148, 2-bromo-lysergic acid diethylamide (179), methysergide, and ergotamine (25).

References

01: Afridi S, Bacon C, Bowling J, Goadsby PJ. Verapamil and lymphomatoid papulosis in chronic cluster headache. J Neurol 2004;251:473-5. PMID 15083295
02: Afridi SK, Goadsby PJ. Neuroimaging of migraine. Current Pain and Headache Reports 2006;10:221-224. PMID 18778577
03: Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injection in primary headache syndromes--prolonged effects from a single injection. Pain 2006;122:126-9. PMID 16527404
04: Ahmed F. Chronic cluster headache responding to gabapentin: a case report. Cephalalgia 2000;20:252-3. PMID 10999675
05: Al-Khazali HM, Deligianni CI, Pellesi L, et al. Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial. Pain 2023. [Epub ahead of print] PMID 38127692
06: Ambrosini A, Vandenheede M, Rossi P, et al. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study. Pain 2005;118:92-6. PMID 16202532
07: Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. Cephalalgia 1986;6:51-4. PMID 3516408
08: Anthony M. Arrest of attacks of cluster headache by local steroid injection of the occipital nerve. In: Rose FC, editor. Migraine: Clinical and Research Advances. London: Karger, 1985:169-73.
09: Antonaci F, Costa A, Candeloro E, Sjaastad O, Nappi G. Single high-dose steroid treatment in episodic cluster headache. Cephalalgia 2005;25(4):290-5. PMID 15773826
10: Antonaci F, Costa A, Ghirmai S, Sances G, Sjaastad O, Nappi G. Parenteral indomethacin (the INDOTEST) in cluster headache. Cephalalgia 2003;23:193-6. PMID 12662186
11: Appelbaum J, Noronha A. Pericarotid cluster headache. J Neurol 1989;236(7):430-1. PMID 2809647
12: Attanasio A, D'Amico D, Frediani F, et al. Trigeminal autonomic cephalgia with periorbital ecchymosis, ocular hemorrhage, hypertension and behavioral alterations. Pain 2000;88:109-12. PMID 11098105
13: Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta Neurol Scand 2004;109:175-9. PMID 14763953
14: Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet 2001;357:1016-7. PMID 11293599
15: Bahra A, May A, Goadsby PJ. Diagnostic trends in cluster headache: an epidemiological study. Cephalalgia 1999;19:431.
16: Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study in 230 patients with diagnostic implications. Neurology 2002;58:354-61. PMID 11839832
17: Bahra A, May A, Goadsby PJ. Diagnostic difficulties in cluster headache: an epidemiological study. Neurology 2000b;54(Suppl 3):A20-1.
18: Barloese M, Jennum P, Lund N, Knudsen S, Gammeltoft S, Jensen R. Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia 2015a;35(10):869-76. PMID 25492975
19: Barloese MC, Jennum PJ, Lund NT, Jensen RH. Sleep in cluster headache - beyond a temporal rapid eye movement relationship? Eur J Neurol 2014;22(4):656-e40. PMID 25557272
20: Barloese M, Lund N, Petersen A, Rasmussen M, Jennum P, Jensen R. Sleep and chronobiology in cluster headache. Cephalalgia 2015b;35(11):969-78.** PMID 25573893
21: Barloese M, Petersen A, Stude P, Jurgens T, Jensen RH, May A. Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry. J Headache Pain 2018;19(1):6. PMID 29349561
22: Baumber L, Sjostrand C, Leone M, et al. A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 2006;66:1888-93. PMID 16801656
23: Benkli B, Kim SY, Koike N, et al. Circadian features of cluster headache and migraine: a systematic review, meta-analysis, and genetic analysis. Neurology 2023;100(22):e2224-36. PMID 36990725
24: Benschop RJ, Collins EC, Darling RJ, et al. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthritis Cartilage 2014;22(4):578-85. PMID 24508775
25: Berde B, Schild HO. Ergot alkaloids and related compounds. In: Born GVR, Eichler O, Farah A, Herken H, Welch AD, eds. Handbook of Experimental Pharmacology vol 49. Berlin: Springer-Verlag, 1978.
26: Bickerstaff ER. The periodic migrainous neuralgia of Wilfred Harris. Lancet 1959;1:1069-71. PMID 13655672
27: Bing R. Uber traumatische Erythromelalgie und Erthroprosopalgie. Der Nervenarzt 1930;3:506-12.
28: Bjork MH, Kristoffersen ES, Tronvik E, Egeland Nordeng HM. Management of cluster headache and other trigeminal autonomic cephalalgias in pregnancy and breastfeeding. Eur J Neurol 2021;28(7):2443-55. PMID 33852763
29: Black DF, Swanson JW, Stang PE. Decreasing incidence of cluster headache: a population-based study in Olmsted County, Minnesota. Headache 2005;45:220-3. PMID 15836596
30: Boes CJ, Matharu MS, Capabioanco DJ, Goadsby PJ. Wilfred Harris' early description of cluster headache. Cephalalgia 2002;22:320-6. PMID 12100097
31: Brandt RB, Cnossen VM, Doesborg PG, et al. Unilateral increased visual sensitivity in cluster headache: a cross-sectional study. Cephalalgia 2022a;42(8):722-9. PMID 35301861
32: Brandt RB, Ouwehand RH, Ferrari MD, Haan J, Fronczek R. COVID-19 vaccination-triggered cluster headache episodes with frequent attacks. Cephalalgia 2022b;42(13):1420-4. PMID 35833226
33: Brittain JS, Green AL, Jenkinson N, et al. Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus. Cephalalgia 2009;29:1165-73. PMID 19366355
34: Burish MJ, Han C, Mawatari K, et al. The first-line cluster headache medication verapamil alters the circadian period and elicits sex-specific sleep changes in mice. Chronobiol Int 2021a;38(6):839-50. PMID 33829951
35: Burish MJ, Pearson SM, Shapiro RE, Zhang W, Schor LI. Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire. Headache 2021b;61(1):117-24.** PMID 33337540
36: Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet 2007;369(9567):1099-106. PMID 17398309
37: Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 2009;72:341-5. PMID 19171831
38: Busch V, Jakob W, Juergens T, Schulte-Mattler W, Kaube H, May A. Functional connectivity between trigeminal and occipital nerves revealed by occipital nerve blockade and nociceptive blink reflexes. Cephalalgia 2006;26(1):50-5. PMID 16396666
39: Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990;30:411-7. PMID 2205598
40: Buture A, Ahmed F, Mehta Y, Paemeleire K, Goadsby PJ, Dikomitis L. Perceptions, experiences, and understandings of cluster headache among GPs and neurologists: a qualitative study in UK primary care. Br J Gen Pract 2020;70(696):e514-e22. PMID 32482627
41: Candeloro E, Canavero I, Maurelli M, et al. Carotid dissection mimicking a new attack of cluster headache. J Headache Pain 2013;14(1):84. PMID 24103794
42: Cevoli S, Pizza F, Grimaldi D, et al. Cerebrospinal fluid hypocretin-1 levels during the active period of cluster headache. Cephalalgia 2011;31:973-6. PMID 21444644
43: Chan C, Goadsby PJ. CGRP pathway monoclonal antibodies for cluster headache. Expert Opinion Biol Ther 2020;20(8):947-53. PMID 32241175
44: Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B. A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984;4:213-20. PMID 6518501
45: Chen SP, Hsu CL, Wang YF, et al. Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan. J Headache Pain 2022;23(1):147. PMID 36404298
46: Chen SP, Takizawa T, Sekiguchi K, Nakahara J, Wang SJ. COVID-19 vaccination elicited de novo and recurrence of cluster headache: a case series. Cephalalgia 2023;43(5):3331024231173354. PMID 37138462
47: Chervin RD, Zellek N, Lin X, Hall JM, Sharma N, Hedger KM. Sleep disordered breathing in patients with cluster headache. Neurology 2000;54:2302-6. PMID 10881257
48: Cho S, Cho SJ, Lee MJ, et al. Clinical characteristics of pre-attack symptoms in cluster headache: A large series of Korean patients. Cephalalgia 2020:41(2):227-36. PMID 33086875
49: Cho S, Cho SJ, Lee MJ, et al. Characteristics of pre-cluster symptoms in cluster headache: a cross-sectional multicentre study. Cephalalgia 2022;42(7):570-8. PMID 35112933
50: Christiansen I, Iversen HK, Olesen J. Induction of nitrate tolerance is not a useful treatment in cluster headache. Cephalalgia 2000;20:445-54. PMID 11037740
51: Chudler EH, Dong WK. The role of the basal ganglia in nociception and pain. Pain 1995;60:33-8. PMID 7715939
52: Cid C, Berciano J, Pascual J. Retro-ocular headache with autonomic features resembling "continuous" cluster headache in a lateral medullary infarction. J Neurol Neurosurg Psychiatry 2000;69:134-41. PMID 10864624
53: Cittadini E, May A, Straube A, Evers S, Bussone G, Goadsby PJ. Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study. Arch Neurol 2006;63(11):1537-42. PMID 16966497
54: Cohen AS, Burns B, Goadsby PJ. High flow oxygen for treatment of cluster headache: a randomized trial. J Am Med Assoc 2009;302:2451-7.** PMID 19996400
55: Cohen AS, Goadsby PJ. Functional neuroimaging of primary headache disorders. Expert Rev Neurother 2006;6(8):1159-71. PMID 16893344
56: Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology 2007;69(7):668-75. PMID 17698788
57: Cosentino G, Brighina F, Brancato S, Valentino F, Indovino S, Fierro B. Transcranial magnetic stimulation reveals cortical hyperexcitability in episodic cluster headache. J Pain 2015;16(1):53-9. PMID 25451628
58: Costa A, Pucci E, Antonaci F, et al. The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia 2000;20:85-91. PMID 10961763
59: Creac'h C, Duthel R, Barral F, et al. Positional cluster-like headache: a case report of a neurovascular compression between the third cervical root and the vertebral artery. Cephalalgia 2010;30:1509-13. PMID 20974591
60: Cremer P, Halmagyi GM, Goadsby PJ. Secondary cluster headache responsive to sumatriptan. J Neurol Neurosurg Psychiatry 1995;59:633-4. PMID 7500105
61: Crespi J, Gulati S, Salvesen Ø, et al. Epidemiology of diagnosed cluster headache in Norway. Cephalalgia Reports 2022;5:25158163221075569.
62: Curran DA, Hinterberger H, Lance JW. Methysergide. Res Clin Stud Headache 1967;1:74-122.
63: D'Alessandro R, Gamberini G, Benassi G, Morganti G, Cortelli P, Lugaresi E. Cluster headache in the Republic of San Marino. Cephalalgia 1986;6:159-62. PMID 3768949
64: D'Amico D, Rigamonti A, Solari A, et al. Health-related quality of life in patients with cluster headache during active periods. Cephalalgia 2002;22:818-21. PMID 12485209
65: DaSilva AF, Goadsby PJ, Borsook D. Cluster headache: a review of neuroimaging findings. Curr Pain Headache Rep 2007;11(2):131-6. PMID 17367592
66: de Coo IF, Wilbrink LA, Ie GD, Haan J, Ferrari MD. Aura in cluster headache: a cross-sectional study. Headache 2018;58(8):1203-10. PMID 29933513
67: Deen M, Hougaard A, Hansen HD, et al. Association between sumatriptan treatment during a migraine attack and central 5-HT1B receptor binding. JAMA Neurol 2019;76(7):834-40. PMID 31135819
68: de L Figuerola M, Bruera O, Leston J, Ferreiro J. Cluster headache attack due to sildenafil intake. Cephalalgia 2006;26:617-9. PMID 16674772
69: de la Sayette V, Schaeffer S, Coskun O, Leproux F, Defer G. Cluster headache-like attack as an opening symptom of a unilateral infarction of the cervical cord: persistent anaesthesia and dysaesthesia to cold stimuli. J Neurol Neurosurg Psychiatry 1999;66:397-400. PMID 10084543
70: Deligianni C, Pellesi L, Chaudhry BA, et al. Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study. Front Neurol 2023;14:1135246. PMID 37143998
71: Demichelis G, Pinardi C, Giani L, et al. Chronic cluster headache: a study of the telencephalic and cerebellar cortical thickness. Cephalalgia 2022;42(6):444-54. PMID 34875879
72: Derbyshire SW, Jones AK, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997;73:431-45. PMID 9469535
73: Diener HC, Tassorelli C, Dodick DW. Management of trigeminal autonomic cephalalgias including chronic cluster: a review. JAMA Neurol 2023;80(3):308-19. PMID 36648786
74: Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: evidence review and clinical implications. Cephalalgia 2019;39(3):445-58. PMID 30661365
75: Dodick DW, Goadsby PJ, Ashina M, et al. Challenges and complexities in designing cluster headache prevention clinical trials: a narrative review. Headache 2022;62(4):453-72. PMID 35363381
76: Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia 2020;40(9):935-48. PMID 32050782
77: Dodick DW, Mosek AC, Campbell JK. The hypnic ("alarm clock") headache syndrome. Cephalalgia 1998;18:152-6. PMID 9595209
78: Dong Z, Di H, Dai W, et al. Clinical profile of cluster headaches in China: a clinic-based study. J Headache Pain 2013;14(1):27. PMID 23574884
79: Donnet A, Carron R, Regis J. Predilection to deafferentation pain syndrome after radiosurgery in cluster headache. Cephalalgia 2012;32(8):635-40. PMID 22529195
80: Donnet A, Lanteri-Minet M, Guegan-Massardier E, et al. Chronic cluster headache: a French clinical descriptive study. J Neurol Neurosurg Psychiatry 2007;78(12):1354-8. PMID 17442761
81: Donnet A, Valade D, Regis J. Gamma knife treatment for refractory cluster headache: prospective open trial. J Neurol Neurosurg Psychiatry 2005;76:218-21. PMID 15654036
82: Drummond PD. Autonomic disturbance in cluster headache. Brain 1988a;111:1199-209. PMID 3179690
83: Drummond PD. Dysfunction of the sympathetic nervous system in cluster headache. Cephalalgia 1988b;8:181-6.** PMID 3197097
84: Drummond PD. Mechanisms of autonomic disturbance in the face during and between attacks of cluster headache. Cephalalgia 2006;26:633-41. PMID 16686902
85: Ekbom K. Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 1968;19:487-93. PMID 4971733
86: Ekbom K. Patterns of cluster headache with a note on the relations to angina pectoris and peptide ulcer. Acta Neurol Scand 1970;46:225-37. PMID 5431456
87: Ekbom K. Lithium in the treatment of chronic cluster headache. Headache 1977;17:39-40. PMID 845026
88: Ekbom K. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache 1981;21:132-9. PMID 7021473
89: Ekbom K, Ahlborg B, Schele R. Prevalence of migraine and cluster headache in Swedish men of 18. Headache 1978;18:9-19. PMID 649381
90: Ekbom K, Greitz T. Carotid angiography in cluster headache. Acta Radiologica 1970;10:177-86. PMID 5491174
91: Ekbom K, Kugelberg E. Upper and lower cluster headache (Horton's syndrome). Brain and Mind. Roma: Il Pensiero Scientifico Editore, 1968:482-9.
92: Ekbom K; The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N Engl J Med 1991;325:322-6. PMID 1647496
93: Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. The Sumatriptan Cluster Headache Study Group. Acta Neurol Scand 1993;88:63-9. PMID 8396833
94: El Amrani M, Ducros A, Boulan P, et al. Familial cluster headache: a series of 186 index patients. Headache 2002a;42:974-7. PMID 12453028
95: El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 2002b;22:205-8. PMID 12047460
96: Ertsey C, Hantos M, Bozsik G, Tekes K. Circulating nociceptin levels during the cluster headache period. Cephalalgia 2004;24:280-3. PMID 15030536
97: Evans RW. Sildenafil can trigger cluster headaches. Headache 2006;46:173-4. PMID 16412168
98: Evers S, Fischera M, May A, Berger K. Prevalence of cluster headache in Germany: results of the epidemiological DMKG study. J Neurol Neurosurg Psychiatry 2007;78(11):1289-90. PMID 17940181
99: Evers S, Quibeldey F, Grotemeyer KH, Suhr B, Husstedt IW. Dynamic changes of cognitive habituation and serotonin metabolism during the migraine interval. Cephalalgia 1999;19:485-91. PMID 10403063
100: Evers S, Soros P, Brilla R, Gerding H, Husstedt IW. Cluster headache after orbital exenteration. Cephalalgia 1997;17(6):680-2. PMID 9350391
101: Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995;60:119-23. PMID 7540279
102: Favier I, Haan J, van Duinen SG, Ferrari MD. Typical cluster headache caused by granulomatous pituitary involvement. Cephalalgia 2007a;27(2):173-6. PMID 17257239
103: Favier I, van Vliet JA, Roon KI, et al. Trigeminal autonomic cephalgias due to structural lesions: a review of 31 cases. Arch Neurol 2007b;64(1):25-31. PMID 17210806
104: Felisati G, Arnone F, Lozza P, Leone M, Curone M, Bussone G. Sphenopalatine endoscopic ganglion block: a revision of a traditional technique for cluster headache. Laryngoscope 2006;116:1447-50. PMID 16885751
105: Ferrari A, Zappaterra M, Righi F, et al. Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. J Headache Pain 2013;14(1):48. PMID 23742010
106: Ferraro S, Nigri A, Bruzzone MG, et al. Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache. Cephalalgia 2018;38(13):1910-8. PMID 29517304
107: Filippini-De Moor GP, Barendse GA, van Kleef M, et al. Retrospective analysis of radiofrequency lesions of the sphenopalatine ganglion in the treatment of 19 cluster headache patients. Pain Clin 1999;11(4):285-91.
108: Fischera M, Anneken K, Evers S. Old age of onset in cluster-headache patients. Headache 2005;45:615. PMID 15953287
109: Fogan L. Treatment of cluster headache: a double blind comparison of oxygen vs air inhalation. Arch Neurol 1985;42:362-3. PMID 3885921
110: Fogh-Andersen IS, Sorensen JCH, Jensen RH, Knudsen AL, Meier K. Treatment of chronic cluster headache with burst and tonic occipital nerve stimulation: a case series. Headache 2023;63(8):1145-53. PMID 37602914
111: Fontaine D, Lazorthes Y, Mertens P, et al. Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. J Headache Pain 2010;11:23-31. PMID 19936616
112: Ford RG, Ford KT, Swaid S, Young P, Jennelle R. Gama knife treatment of refractory cluster headache. Headache 1998;38:3-9. PMID 9504996
113: Forderreuther S, Mayer M, Straube A. Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia 2002;22(3):186-9. PMID 12047455
114: Formisano R, Angelini A, De Vuono G, et al. Cluster-like headache and head injury: case report. Ital J Neurol Sci 1990;11(3):303-5. PMID 2387704
115: Fourier C, Ran C, Steinberg A, Sjostrand C, Waldenlind E, Belin AC. Sex differences in clinical features, treatment, and lifestyle factors in patients with cluster headache. Neurology 2023;100(12):e1207-20. PMID 36543572
116: Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery 2003;52:1095-101. PMID 12699552
117: Frederiksen HH, Lund NL, Barloese MC, Petersen AS, Jensen RH. Diagnostic delay of cluster headache: a cohort study from the Danish Cluster Headache Survey. Cephalalgia 2020;40(1):49-56. PMID 31291778
118: Friedman AP, Mikropoulos HE. Cluster headaches. Neurology 1958;8:653-63. PMID 13578060
119: Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache 1989;29:167-8. PMID 2708046
120: Gaul C, Christmann N, Schroder D, et al. Differences in clinical characteristics and frequency of accompanying migraine features in episodic and chronic cluster headache. Cephalalgia 2012;32(7):571-7. PMID 22529192
121: Gaul C, Diener HC, Silver N, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia 2015;36(6):534-46. PMID 26391457
122: Gaul C, Jurgens T. Frovatriptan for prophylactic treatment of cluster headache. Headache 2011;51:1008-9. PMID 21453330
123: Gawel MJ, Willinsky RA, Krajewski A. Reversal of cluster headache side following treatment of arteriovenous malformation. Headache 1989;29(7):453-4. PMID 2759853
124: Geerlings RP, Haane DY, Koehler PJ. Rebound following oxygen therapy in cluster headache. Cephalalgia 2011;31:1145-9. PMID 21700644
125: Gelfand AA, Goadsby PJ. The role of melatonin in the treatment of primary headache disorders. Headache 2016;56(8):1257-66.** PMID 27316772
126: Geweke LO. Misdiagnosis of cluster headache. Curr Pain Headache Rep 2002;6:76-82. PMID 11749882
127: Giani L, Cecchini AP, Astengo A, Lauria G, Leone M. Cluster headache not responsive to sumatriptan: a retrospective study. Cephalalgia 2021;41(1):117-21. PMID 32883087
128: Gil-Gouveia R, Fonseca A. Cluster headache after cataract surgery. Clin J Pain 2013;29(11):e19-21. PMID 23486235
129: Giraud P, Chauvet S. Cluster headache during pregnancy: case report and literature review. Headache 2009;49:136-9. PMID 19125883
130: Goadsby PJ. Cluster headache and the clinical profile of sumatriptan. Eur Neurol 1994;34(Suppl):35-9. PMID 7835381
131: Goadsby PJ. Cluster headache and the trigeminal-autonomic reflex: driving or being driven? Cephalalgia 2018;38(8):1415-7. PMID 29082825
132: Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol 2002a;1:37-43. PMID 12849458
133: Goadsby PJ. Raeders syndrome: "paratrigeminal" paralysis of oculo-pupillary sympathetic. J Neurol Neurosurg Psychiatry 2002b;72:297-9. PMID 11861683
134: Goadsby PJ. Trigeminal autonomic cephalalgias (TACs). In: Shapira AH, editor. Neurology and Clinical Neuroscience. Philadelphia: Mosby Elsevier, 2007:773-91.
135: Goadsby PJ, Cohen AS, Matharu MS. Trigeminal autonomic cephalalgias: diagnosis and treatment. Curr Neurol Neurosci Rep 2007;7(2):117-25. PMID 17355838
136: Goadsby PJ, de Coo I, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018;38(5):959-69. PMID 29231763
137: Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med 2019a;381(2):132-41.** PMID 31291515
138: Goadsby PJ, Duckworth JW. Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats. Am J Physiol 1987;253:R270-4. PMID 3497587
139: Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 1994;117:427-34.** PMID 7518321
140: Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain 1997;120:193-209.** PMID 9055807
141: Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, et al. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind randomised controlled trial. Lancet Neurology 2019b;18(12):1081-90.** PMID 31701891
142: Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia 2006;26(9):1168-70. PMID 16919073
143: Godeiro-Junior C, Kuster GW, Felicio AC, Porto PP Jr, Pieri A, Coelho FM. Internal carotid artery dissection presenting as cluster headache. Arq Neuropsiquiatr 2008;66:763-4. PMID 18949282
144: Gordon A, Roe T, Villar-Martinez MD, Moreno-Ajona D, Goadsby PJ, Hoffmann J. Effectiveness and safety profile of greater occipital nerve blockade in cluster headache: a systematic review. J Neurol Neurosurg Psychiatry 2023;95(1):73-85. PMID 36948579
145: Gorgoni M, Giuliani G, Fratino M, Di Piero V. The objective assessment of sleep in cluster headache: state of the art and future directions. J Sleep Res 2023:e14103. PMID 37963453
146: Gould JD, Silberstein SD. Unilateral hypnic headache: a case study. Neurology 1997;49:1749-51. PMID 9409389
147: Graff-Radford SB, Newman A. Obstructive sleep apnea and cluster headache. Headache 2004;44:607-10. PMID 15186306
148: Greve E, Mai J. Cluster headache-like headaches: a symptomatic feature. A report of three patients with intracranial pathologic findings. Cephalalgia 1988;8:79-82. PMID 3401920
149: Guo S, Petersen A, Schytz HW, et al. Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks. Cephalalgia 2018;38(8):1418-28. PMID 29082824
150: Haan J, van Vliet JA, Kors EE, et al. No involvement of calcium channel gene (CACNA1A) in a family with cluster headache. Cephalalgia 2001;21:959-62. PMID 11843867
151: Hambach A, Evers S, Summ O, Husstedt IW, Frese A. The impact of sexual activity on idiopathic headaches: an observational study. Cephalalgia 2013;33(6):384-9. PMID 23430983
152: Hannerz J. A case of parasellar meningioma mimicking cluster headache. Cephalalgia 1989;9:265-9. PMID 2611884
153: Hardebo JE. How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibres. Headache 1994;34:125-31. PMID 8200785
154: Harder AVE, Winsvold BS, Noordam R, et al. Genetic susceptibility loci in genomewide association study of cluster headache. Ann Neurol 2021;90(2):203-16.** PMID 34180076
155: Harris W. Ciliary (migrainous) neuralgia and its treatment. Br Med J 1936;1:457-60. PMID 20779792
156: Headache Classification Committee of The International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1-96. PMID 3048700
157: Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders. Second ed. Cephalalgia 2004;24(Suppl 1):1-160. PMID 14979299
158: Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1-211. PMID 29368949
159: Heidegger S, Mattfeldt T, Rieber A, et al. Orbito-sphenoidal aspergillus infection mimicking cluster headache: a case report. Cephalalgia 1997;17:676-9. PMID 9350390
160: Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 1989;9:195-8. PMID 2507161
161: Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol 2018;17(1):75-83.** PMID 29174963
162: Hofman MA, Zhou JN, Swaab DF. Suprachiasmatic nucleus of the human brain: an immunocytochemical and morphometric analysis. Anat Rec 1996;244(4):552-62. PMID 8694290
163: Holland PR, Goadsby PJ. Cluster headache, hypothalamus, and orexin. Curr Pain Headache Rep 2009;13:147-54. PMID 19272281
164: Holle D, Gaul C, Zillessen S, et al. Lateralized central facilitation of trigeminal nociception in cluster headache. Neurology 2012a;78(13):985-92. PMID 22422891
165: Holle D, Zillessen S, Gaul C, et al. Habituation of the nociceptive blink reflex in episodic and chronic cluster headache. Cephalalgia 2012b;32(13):998-1004. PMID 22807570
166: Horton BT. Histaminic cephalgia. Lancet 1952;72:92-8. PMID 14908316
167: Horton BT. Histaminic cephalalgia: differential diagnosis and treatment. Mayo Clin Proc 1956;31:325-33. PMID 13323056
168: Horton BT, MacLean AR, Craig WM. A new syndrome of vascular headache; results of treatment with histamine; a preliminary report. Mayo Clin Proc 1939;14:250-7.
169: Irimia P, Cittadini E, Paemeleire K, Cohen AS, Goadsby PJ. Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias. Cephalalgia 2008;28:626-30. PMID 18422722
170: Isler H. Episodic cluster headache from a textbook of 1745: Van Swieten's classic description. Cephalalgia 1993;13:172-4. PMID 8358775
171: Ivanez V, Soler R, Barreiro P. Hypnic headache syndrome: a case with good response to indomethacin. Cephalalgia 1998;18(4):225-6. PMID 9642499
172: Ivanusic JJ, Kwok MM, Ahn AH, Jennings EA. 5-HT(1D) receptor immunoreactivity in the sphenopalatine ganglion: implications for the efficacy of triptans in the treatment of autonomic signs associated with cluster headache. Headache 2011;51:392-402. PMID 21352213
173: Jammes JL. The treatment of cluster headaches with prednisone. Dis Nerv Sys 1975;36:375-6. PMID 1097222
174: Jarrar RG, Black DF, Dodick DW, Davis DH. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 2003;60:1360-2. PMID 12707445
175: Jensen RH, Tassorelli C, Myers Oakes TM, et al. Baseline demographics and disease characteristics of patients with episodic or chronic cluster headache: data from two phase 3 randomized clinical trials in Europe and North America. Front Neurol 2023;14:1293163. PMID 38162453
176: Jurgens TP, Barloese M, May A, et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 2017;37(5):423-34. PMID 27165493
177: Kamm K, Straube A, Ruscheweyh R. Baseline tear fluid CGRP is elevated in active cluster headache patients as long as they have not taken attack abortive medication. Cephalalgia 2021;41(1):69-77. PMID 32847402
178: Karsan N, Nagaraj K, Goadsby PJ. Cranial autonomic symptoms: prevalence, phenotype and laterality in migraine and two potentially new symptoms. J Headache Pain 2022;23(1):18.** PMID 35093009
179: Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. Cephalalgia 2010;30:1140-4. PMID 20713566
180: Kawazoe Y, Kumon M, Tateyama S, Moriya S. Efficacy of cabergoline and triptans for cluster-like headache caused by prolactin-secreting pituitary adenoma: a literature review and case report. Clin Neurol Neurosurg 2020;196:106005. PMID 32599424
181: Khatami R, Tartarotti S, Siccoli MM, Bassetti CL, Sandor PS. Long-term efficacy of sodium oxybate in 4 patients with chronic cluster headache. Neurology 2011;77:67-70. PMID 21613599
182: Kirkpatrick PJ, O'Brien M, MacCabe JJ. Trigeminal nerve section for chronic migrainous neuralgia. Br J Neurosurg 1993;7:483-90. PMID 7505590
183: Kitrelle JP, Grouse DS, Seybold ME. Cluster headache: local anesthetic abortive agents. Arch Neurol 1985;42:496-8. PMID 3994568
184: Koehler PJ. Prevalence of headache in Tulp's observationes medicae (1641) with a description of cluster headache. Cephalalgia 1993;13:318-20. PMID 8242723
185: Koenigsberg AD, Solomon GD, Kosmorsky DO. Pseudoaneurysm within the cavernous sinus presenting as cluster headache. Headache 1994;34:111-3. PMID 8163366
186: Kudrow D, Andrews JS, Rettiganti M, et al. Treatment outcomes in patients treated with galcanezumab vs placebo: post hoc analyses from a phase 3 randomized study in patients with episodic cluster headache. Headache 2020;60(10):2254-64. PMID 33179263
187: Kudrow L. Plasma testosterone levels in cluster headache preliminary results. Headache 1976;16:228-31. PMID 1254468
188: Kudrow L. Lithium prophylaxis for chronic cluster headache. Headache 1977a;17:15-8. PMID 845021
189: Kudrow L. Plasma testosterone and LH levels in cluster headache. Headache 1977b;17:91-2.
190: Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981;21:1-4. PMID 7007285
191: Kudrow L, McGinty DJ, Phillips ER, Stevenson M. Sleep apnea in cluster headache. Cephalalgia 1984;4:33-8. PMID 6713522
192: Kunkle EC, Pfieffer JB Jr, Wilhoit WM, Hamrick LW Jr. Recurrent brief headache in cluster pattern. Trans Am Neurol Assoc 1952;27:240-3. PMID 13038844
193: Kuritzky A. Cluster headache-like pain caused by an upper cervical meningioma. Cephalalgia 1984;4:185-6. PMID 6498932
194: Lainez MJ, Pascual J, Pascual AM, Santonja JM, Ponz A, Salvador A. Topiramate in the prophylactic treatment of cluster headache. Headache 2003;43:784-49. PMID 12890134
195: Lampl C. Childhood-onset cluster headache. Pediatr Neurol 2002;27:138-40. PMID 12213616
196: Lance JW, Anthony M. Migrainous neuralgia or cluster headache. J Neurol Sci 1971;13:401-14. PMID 25272263
197: Lance JW, Goadsby PJ. Mechanism and Management of Headache. 7th ed. New York: Elsevier, 2005.
198: Langedijk M, van der Naalt J, Luijckx GJ, De Keyser J. Cluster-like headache aura status. Headache 2005;45:80-1. PMID 15663619
199: Lanteri-Minet M, Silhol F, Piano V, Donnet A. Cardiac safety in cluster headache patients using the very high dose of verapamil (>/=720 mg/day). J Headache Pain 2011;12:173-6. PMID 21258839
200: Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug-resistant cluster headache responding to gabapentin: a pilot study. Cephalalgia 2001;21:744-6. PMID 11595003
201: Lee MJ, Cho SJ, Park JW, et al. Temporal changes of circadian rhythmicity in cluster headache. Cephalalgia 2020;40(3):278-87. PMID 31623453
202: Lee MJ, Park JW, Chu MK, et al. Treatment pattern and response for cluster headache in Korea: a prospective multicenter observation study. Cephalalgia 2023;43(4):3331024231159627. PMID 36855967
203: Lefevre JP, Simmat G, Bataille B, et al. [Cluster headache due to meningioma. 2 cases]. Presse Med 1984;13(38):2323. PMID 6239193
204: Leone M, Bussone G. Melatonin in cluster headache--rationale for use and possible therapeutic potential. CNS Drugs 1998;9:7-16.
205: Leone M, Proietti Cecchini AP. Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache. Neurology (Minneap) 2016;86(2):194-5. PMID 26475695
206: Leone M, D'Amico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 2000;54(6):1382-5. PMID 10746617
207: Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996;16:494-6. PMID 8933994
208: Leone M, Dodick D, Rigamonti A, et al. Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia 2003;23:1001-2. PMID 14984235
209: Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology 2006;67:150-2. PMID 16832097
210: Leone M, Franzini A, Broggi G, May A, Bussone G. Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache. Brain 2004;127:2259-64. PMID 15329350
211: Leone M, Lucini V, Damico D, et al. Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia 1998;18:664-7. PMID 9950622
212: Leone M, Partuno G, Vescovi A, Bussone G. Neuroendocrine dysfunction in cluster headache. Cephalalgia 1990;10:235-9. PMID 2272093
213: Leone M, Russell MB, Rigamonti A, et al. Increased familial risk of cluster headache. Neurology 2001;56:1233-6. PMID 11342697
214: Leplus A, Fontaine D, Donnet A, et al. Long-term efficacy of occipital nerve stimulation for medically intractable cluster headache. Neurosurgery 2021;88(2):375-83. PMID 32985662
215: Leroux E, Taifas I, Valade D, Donnet A, Chagnon M, Ducros A. Use of cannabis among 139 cluster headache sufferers. Cephalalgia 2013;33(3):208-13. PMID 23197349
216: Leroux E, Valade D, Taifas I, et al. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2011;10:891-7. PMID 21903477
217: Levy MJ, Barakat M, Bejon P, Goadsby PJ, Meeran K. Acromegaly:a unique human headache model. Headache 2003;43:794-7. PMID 12890136
218: Levy MJ, Jager HR, Powell M, Matharu MS, Meeran K, Goadsby PJ. Pituitary volume and headache: size is not everything. Arch Neurol 2004;61(5):721-5. PMID 15148150
219: Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005;128(Pt 8):1921-30. PMID 15888539
220: Levy MJ, Robertson I, Howlett TA. Cluster headache secondary to macroprolactinoma with ipsilateral cavernous sinus invasion. Case Report Neurol Med 2012;2012:830469. PMID 2036668
221: Levyman C, Dagua Filho Ados S, Volpato MM, Settanni FA, de Lima WC. Epidermoid tumour of the posterior fossa causing multiple facial pain--a case report. Cephalalgia 1991;11(1):33-6. PMID 2036668
222: Liaw YC, Wang YF, Chen WT, et al. Sex-related differences in cluster headache: a hospital-based study in Taiwan. Cephalalgia 2022;42(14):1532-42. PMID 36003003
223: Lin H, Dodick DW. Tearing without pain after trigeminal root section for cluster headache. Neurology 2005;65:1650-1. PMID 16301498
224: Lodi R, Pierangeli G, Tonon C, et al. Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 2006;66:1264-6. PMID 16636250
225: Lund N, Barloese M, Petersen A, Haddock B, Jensen R. Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology 2017;88(11):1069-76. PMID 28202701
226: Mack KJ, Goadsby P. Trigeminal autonomic cephalalgias in children and adolescents- cluster headache and related conditions. Semin Pediatr Neurol 2016;23(1):23-6. PMID 27017018
227: Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol 2007;6(4):314-21. PMID 17362835
228: Magis D, Bruno MA, Fumal A, et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol 2011a;11:25. PMID 21349186
229: Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache 2011b;51(8):1191-201. PMID 21848953
230: Mainardi F, Maggioni F, Dainese F, Amista P, Zanchin G. Spontaneous carotid artery dissection with cluster-like headache. Cephalalgia 2002;22:557-9. PMID 12230599
231: Mani S, Deeter J. Arteriovenous malformation of the brain presenting as a cluster headache: a case report. Headache 1982;22:184-5. PMID 7107248
232: Manzoni GC. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia 1998;18:138-42. PMID 9595206
233: Manzoni GC, Maffezzoni M, Lambru G, Lana S, Latte L, Torelli P. Late-onset cluster headache: some considerations about 73 cases. Neurol Sci 2012;33 Suppl 1:S157-9. PMID 22644193
234: Manzoni GC, Micieli G, Granella F, Tassorelli C, Zanferrari C, Cavallini A. Cluster headache- course over ten years in 189 patients. Cephalalgia 1991;11:169-74. PMID 1742772
235: Marks DR, Rapoport A, Padla D. A double-blind placebo-controlled trial of intra-nasal capsaicin for cluster headache. Cephalalgia 1993;13:114-6. PMID 8495452
236: Marmura MJ, Pello SJ, Young WB. Interictal pain in cluster headache. Cephalalgia 2010;30:1531-4. PMID 20974600
237: Martins IP, Gouveia RG, Antunes JL. Double dissociation between autonomic symptoms and pain in cluster headache. Cephalalgia 2005;25(5):398-400. PMID 15839856
238: Massie R, Sirhan D, Andermann F. Chronic cluster-like headache secondary to an epidermoid clival lesion. Can J Neurol Sci 2006;33(4):421-2. PMID 17168171
239: Matharu MS, Goadsby PJ. Persistence of attacks of cluster headache after trigeminal nerve root section. Brain 2002;175:976-84. PMID 11960888
240: Mather P, Silberstein SD, Schulman E, Hopkins MM. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache 1991;31:525-32. PMID 1960057
241: Mathew NT. Clinical subtypes of cluster headache and response to lithium therapy. Headache 1978;18:26-30. PMID 649376
242: Mathew NT, Hurt W. Percutaneous radiofrequency trigeminal gangliorhizolysis in intractable cluster headache. Headache 1988;28:328-31. PMID 3261287
243: May A. Illicit drugs and cluster headache: An inevitable discussion. Cephalalgia 2012;32(14):1021-2.** PMID 23043132
244: May A, Ashburner J, Buchel C, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999a;5:836-8. PMID 10395332
245: May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet 1998a;352:275-8. PMID 9690407
246: May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000a;55:1328-35. PMID 11087776
247: May A, Buchel C, Bahra A, Goadsby PJ, Frackowiak RS. Intra-cranial vessels in trigeminal transmitted pain: a PET Study. Neuroimage 1999b;9:453-60. PMID 10329285
248: May A, Buchel C, Frackowiak RS, Goadsby PJ. Visualizing the subjective degree of pain using functional imaging. Cephalalgia 2000b;20:278.
249: May A, Buchel C, Turner R, Goadsby PJ. MR-angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation. J Cereb Blood Flow Metab 2001;21:1171-6. PMID 11598494
250: May A, Evers S, Goadsby PJ, et al. European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol 2023;30(10):2955-79.** PMID 37515405
251: May A, Kaube H, Buechel C, et al. Experimental cranial pain elicited by capsaicin: a PET-study. Pain 1998b;74:61-6. PMID 9514561
252: May A, Leone M, Boecker H, et al. Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci 2006;26:3589-93. PMID 16571767
253: May A, Shepheard S, Wessing A, Hargreaves RJ, Goadsby PJ, Diener HC. Retinal plasma extravasation can be evoked by trigeminal stimulation in rat but does not occur during migraine attacks. Brain 1998c;121:1231-7. PMID 9679775
254: McClure-Begley TD, Roth BL. The promises and perils of psychedelic pharmacology for psychiatry. Nat Rev Drug Discov 2022;21(6):463-73. PMID 35301459
255: McKinney AS. Cluster headache developing following ipsilateral orbital exenteration. Headache 1983;23(6):305-6. PMID 6643039
256: McNabb S, Whitehouse W. Cluster headache-like disorder in childhood. Arch Dis Child 1999;81(6):511-2. PMID 10569970
257: Membrilla JA, Torres-Ferrus M, Alpuente A, Caronna E, Pozo-Rosich P. Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: case series and narrative review. Headache 2022;62(10):1395-405. PMID 36321947
258: Merli E, Rustici A, Gramegna LL, et al. Vessel-wall MRI in primary headaches: the role of neurogenic inflammation. Headache 2023;63(10):1372-9. PMID 35137395
259: Messina R, Sudre CH, Wei DY, Filippi M, Ourselin S, Goadsby PJ. Biomarkers of migraine and cluster headache: differences and similarities. Ann Neurol 2023;93(4):729-42. PMID 36565271
260: Mjaset C, Russell MB. Secondary chronic cluster headache due to trigeminal nerve root compression. Acta Neurol Scand 2010;122:373-6. PMID 20384588
261: Molins A, Lopez M, Codina A, Titus F. [Symptomatic cluster headache. Apropos of 4 case reports]. Med Clin (Barc) 1989;92(5):181-3. PMID 2725106
262: Moller M, Haji AA, Hoffmann J, May A. Peripheral provocation of cranial autonomic symptoms is not sufficient to trigger cluster headache attacks. Cephalalgia 2018;38(8):1498-502. PMID 29082823
263: Monstad I, Krabbe A, Micieli G, et al. Preemptive oral treatment with sumatriptan during a cluster period. Headache 1995;35:607-13. PMID 8550362
264: Montagna P, Cortelli P, Barbiroli B. A case of cluster headache associated with mitochondrial DNA deletions. Muscle Nerve 1998a;21(1):127-8. PMID 9427236
265: Montagna P, Mochi M, Prologo G, et al. Heritability of cluster headache. Eur J Neurol 1998b;5:343-5.
266: Moore RY. Circadian rhythms: basic neurobiology and clinical applications. Ann Rev Med 1997;48:253-66. PMID 9046960
267: Moore-Ede MC. The circadian timing system in mammals: two pacemakers preside over many secondary oscillators. Fed Proc 1983;42:2802-8. PMID 6873308
268: Morales-Asin F, Mauri JA, Iniguez C, Espada F, Mostacero E. The hypnic headache syndrome: report of three new cases. Cephalagia 1998;18:157-8. PMID 9595210
269: Morelli N, Pesaresi I, Cafforio G, et al. Functional magnetic resonance imaging in episodic cluster headache. J Headache Facial Pain 2009;10:11-4. PMID 19083151
270: Mosek A, Hering-Hanit R, Kuritzky A. New-onset cluster headache in middle-age and elderly women. Cephalalgia 2001;21:198-200. PMID 11442554
271: Moskowitz MA. Cluster headache: evidence for a pathophysiologic focus in the superior pericarotid cavernous sinus plexus. Headache 1988;28:584-6. PMID 3074069
272: Moskowitz MA, Cutrer FM. SUMATRIPTAN: a receptor-targeted treatment for migraine. Ann Rev Med 1993;44:145-54. PMID 8386498
273: Mueller OM, Gaul C, Katsarava Z, Diener HC, Sure U, Gasser T. Occipital nerve stimulation for the treatment of chronic cluster headache - lessons learned from 18 months experience. Cen Eur Neurosurg 2011;72:84-9. PMID 21448856
274: Munoz C, Diez-Tejedor E, Frank A, Barreiro P. Cluster headache syndrome associated with middle cerebral artery arteriovenous malformation. Cephalalgia 1996;16:202-5. PMID 8734773
275: Muzzi M, Zecchi R, Ranieri G, et al. Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: implication for cluster headache treatment. Cephalalgia 2020;40(4):330-6. PMID 31852231
276: Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology 2011;77(20):1827-32. PMID 22049203
277: Narouze S, Kapural L, Casanova J, Mekhail N. Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache. Headache 2009;49(4):571-7. PMID 18783451
278: Naylor WG. Calcium Antagonists. London: Academic Press, 1988.
279: Negoro K, Kawai M, Tada Y, Ogasawara J, Misumi S, Morimatsu M. A case of postprandial cluster-like headache with prolactinoma: dramatic response to cabergoline. Headache 2005;45(5):604-6. PMID 15953282
280: Nesbitt AD, Goadsby PJ. Cluster headache. BMJ 2012;344:e2407. PMID 22496300
281: Nesbitt AD, Marin JCA, Tompkins E, Ruttledge MH, Goadsby PJ. Initial experience with a novel non-invasive vagus nerve stimulation device for the treatment of cluster headache. Neurology (Minneap) 2015;84:1-5. PMID 25713002
282: Newman LC, Lipton RB, Solomon S. The hypnic headache syndrome: a benign headache disorder of the elderly. Neurology 1990;40:1904-5. PMID 2123309
283: Nilsson Remahl AI, Ansjon R, Lind F, Waldenlind E. Hyperbaric oxygen treatment of active cluster headache: a double-blind placebo-controlled cross-over study. Cephalalgia 2002;22:730-9. PMID 12421159
284: Nilsson Remahl AI, Laudon Meyer E, Cordonnier CS, Goadsby PJ. Placebo response rates in cluster headache trials: a review. Cephalalgia 2003;23:504-10. PMID 12950375
285: Nobre ME, Filho PF, Dominici M. Cluster headache associated with sleep apnoea. Cephalalgia 2003;23:276-9. PMID 12716345
286: Nobre ME, Leal AJ, Filho PM. Investigation into sleep disturbance of patients suffering from cluster headache. Cephalalgia 2005;25:488-92. PMID 15955035
287: Nowacki A, Schober M, Nader L, et al. Deep brain stimulation for chronic cluster headache: meta-analysis of individual patient data. Ann Neurol 2020;88(5):956-69. PMID 32827225
288: Obermann M, Nagel S, Ose C, et al. Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial. Lancet Neurol 2021;20(1):29-37. PMID 33245858
289: O'Connor E, Fourier C, Ran C, et al. Genome-wide association study identifies risk loci for cluster headache. Ann Neurol 2021;90(2):193-202. PMID 34184781
290: Olesen J, Goadsby PJ. Cluster headache and related conditions. Oleson J, editor. In: Frontiers in Headache Research. Volume 9. Oxford: Oxford University Press, 1999.
291: Olivarius de Fine B. Hemicrania neuralgiformis chronica (Chronic migrainous neuralgia). In: Quoted by Sjaastad, ed. Proceedings of the Scandinav Migraine Society Annual Meeting, 1971:8.
292: Onofrio BM, Campbell JK. Surgical treatment of chronic cluster headache. Proc Mayo Clin 1986;61:537-41. PMID 2423815
293: Oomen K, Wijck A, Hordijk G, Ru J. Microvascular decompression of the pterygopalatine ganglion in patients with refractory cluster headache. Cephalalgia 2011;31:1236-9. PMID 21765148
294: Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in cluster headache patients. Neurology 2006;67:109-13. PMID 16832088
295: Palma JA, Palma F. A probable cluster headache case from a textbook of 1726: Francisco Suarez de Rivera's description. Cephalalgia 2011;31:1232-5. PMID 21768182
296: Papasavva M, Katsarou MS, Vikelis M, et al. Analysis of HCRTR2, GNB3, and ADH4 gene polymorphisms in a Southeastern European Caucasian cluster headache population. J Mol Neurosci 2019. PMID 31768945
297: Pedersen AS, Snoer A, Barloese M, Petersen A, Jensen RH. Prevalence of pre-cluster symptoms in episodic cluster headache: is it possible to predict an upcoming bout? Cephalalgia 2021;41(7):799-809.** PMID 33472428
298: Pellesi L, Chaudhry BA, Vollesen ALH, et al. PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation. Cephalalgia 2022;42(8):687-95. PMID 34822741
299: Penarrocha M, Bagan JV, Penarrocha MA, Silvestre FJ. Cluster headache and cocaine use. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:271-4. PMID 10982945
300: Penarrocha M, Bandres A, Penarrocha MA, Bagan JV. Relationship between oral surgical and endodontic procedures and episodic cluster headache. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:499-502. PMID 11709684
301: Peng KP, Schellong M, May A. Aura in trigeminal autonomic cephalalgia is probably mediated by comorbid migraine with aura. Cephalalgia 2022;42(1):31-6. PMID 34407649
302: Peres MF, Rozen TD. Melatonin in the preventative treatment of chronic cluster headache. Cephalalgia 2001;21:993-5. PMID 11843873
303: Petersen AS, Barloese MC, Lund NL, Jensen RH. Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study. Cephalalgia 2017;37(3):214-24. PMID 27013239
304: Petersen AS, Barloese M, Lund N, et al. Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response. Eur J Neurol 2023;30(5):1425-34. PMID 36773010
305: Pieper DR, Dickerson J, Hassenbusch SJ. Percutaneous retrogasserian glycerol rhizolysis for treatment of chronic intractable cluster headaches: long-term results. Neurosurgery 2000;46(2):363-8. PMID 10690725
306: Pietzsch JB, Weber SA, Lund N, Gaul C. Changes in medication cost observed in chronic cluster headache patients treated with sphenopalatine ganglion (SPG) stimulation: analysis based on 1-year data from the Pathway R-1 Registry. Cephalalgia 2018;38(8):1455-62. PMID 29921140
307: Pipolo C, Bussone G, Leone M, Lozza P, Felisati G. Sphenopalatine endoscopic ganglion block in cluster headache: a reevaluation of the procedure after 5 years. Neurol Sci 2010;31(Suppl 1):S197-9. PMID 20464621
308: Prakash S, Shah ND, Chavda BV. Cluster headache responsive to indomethacin: case reports and a critical review of the literature. Cephalalgia 2010;30:975-82. PMID 20656709
309: Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache 2002;42:787-92. PMID 12390642
310: Prusinski A, Liberski PP, Szulc-Kuberska J. Cluster headache in a patient without a ipsilateral eye. Headache 1985;25(3):134-5. PMID 4008249
311: Qiu E, Wang Y, Ma L, et al. Abnormal brain functional connectivity of the hypothalamus in cluster headaches. PLoS One 2013;8(2):e57896. PMID 23460913
312: Rainero I, Gallone S, Rubino E, et al. Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache. Headache 2008;48:1108-14. PMID 18399985
313: Rainero I, Gallone S, Valfre W, et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 2004;63:1286-8. PMID 15477554
314: Rapoport AM, Bigal ME, Tepper SJ, Sheftell FD. Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia 2003;23:69-70. PMID 12534585
315: Rapoport AM, Mathew NT, Silberstein SD, et al. Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study. Neurology 2007;69(9):821-6. PMID 17724283
316: Raskin NH. The hypnic headache syndrome. Headache 1988;28:534-6. PMID 3198388
317: Razvi SS, Walker L, Teasdale E, Tyagi A, Muir KW. Cluster headache due to internal carotid artery dissection. J Neurol 2006;253(5):661-3. PMID 16541217
318: Remahl IN, Waldenlind E, Bratt J, Ekbom K. Cluster headache is not associated with signs of a systemic inflammation. Headache 2000;40(4):276-81. PMID 10759931
319: Riesenberg R, Gaul C, Stroud CE, et al. Long-term open-label safety study of galcanezumab in patients with episodic or chronic cluster headache. Cephalalgia 2022;42(11-12):1225-35. PMID 35633025
320: Riess CM, Becker WJ, Robertson M. Episodic cluster headache in a community: clinical features and treatment. Can J Neurol Sci 1998;25(2):141-5. PMID 9604136
321: Rocca MA, Valsasina P, Absinta M, et al. Central nervous system dysregulation extends beyond the pain-matrix network in cluster headache. Cephalalgia 2010;30:1383-91. PMID 20959433
322: Rogado AZ, Graham JR. Through a glass darkly. Headache 1979;19(2):58-62. PMID 422349
323: Romberg MH. Lehrbuch der Nervenkrankheiten des Menschen. Volume 1. Berlin: Dunker, 1840.
324: Romoli M, Cudia G. Cluster headache due to an impacted superior wisdom tooth: case report. Headache 1988;28(2):135-6. PMID 3372240
325: Rosebraugh CJ, Griebel DJ, DiPette DJ. A case report of carotid artery dissection presenting as cluster headache. Am J Med 1997;102(4):418-9. PMID 9217627
326: Rossi P, Allena M, Tassorelli C, et al. Illicit drug use in cluster headache patients and in the general population: A comparative cross-sectional survey. Cephalalgia 2012;32(14):1031-40. PMID 22967729
327: Rossi P, Lorenzo GD, Formisano R, Buzzi MG. Subcutaneous sumatriptan induces changes in frequency pattern in cluster headache patients. Headache 2004;44:713-8. PMID 15209695
328: Rozen TD. Olanzapine as an abortive agent for cluster headache. Headache 2001;41:813-6. PMID 11576207
329: Rozen TD. Childhood exposure to second-hand tobacco smoke and the development of cluster headache. Headache 2005;45:393-4. PMID 15836583
330: Rozen TD, Niknam RM, Shechter AL, Young WB, Silberstein SD. Cluster headache in women: clinical characteristics and comparison with cluster headache in men. J Neurol Neurosurg Psychiatry 2001;70:613-7. PMID 11309454
331: Ruscheweyh R, Broessner G, Gossrau G, et al. Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts. Cephalalgia 2020;40(14):1574-84. PMID 32806953
332: Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol 2004;3:279-83.** PMID 15099542
333: Russell MB, Andersson PG, Iselius L. Cluster headache is an inherited disorder in some families. Headache 1996;36:608-12. PMID 8990601
334: Russell MB, Andersson PG, Thomsen LL, Iselius L. Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J Med Genet 1995;32:954-6. PMID 8825923
335: Sacquegna T, D'Alessandro R, Cortelli P, De Carolis P, Baldrati A. Cluster headache after herpes zoster ophthalmicus. Arch Neurol 1982;39(6):384. PMID 7092621
336: Sandor PS, Irimia P, Jager HR, Goadsby PJ, Kaube H. Onset of cluster headache triggered by emotional effect: a case report. J Neurol Neurosurg Psychiatry 2006;77:1097-9. PMID 16914764
337: Sandrini G, Antonaci F, Lanfranchi S, Milanov I, Danilov A, Nappi G. Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache. Cephalalgia 2000;20(7):647-52. PMID 11128822
338: Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol 2002;59:990-4. PMID 12056936
339: Schankin CJ, Reifferscheid AK, Krumbholz M, et al. Headache in patients with pituitary adenoma: Clinical and paraclinical findings. Cephalalgia 2012;32(16):1198-207. PMID 23059488
340: Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: results from a randomized, double-blind, placebo-controlled trial. Headache 2022;62(10):1383-94. PMID 36416492
341: Schoenen J, Di Clemente L, Vandenheede M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 2005;128:940-7. PMID 15689358
342: Schoenen J, Jensen RH, Lanteri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment- Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 2013;33:816-30.** PMID 23314784
343: Schuh-Hofer S, Richter M, Israel H, et al. The use of radiolabelled human serum albumin and SPECT/MRI co-registration to study inflammation in the cavernous sinus of cluster headache patients. Cephalalgia 2006(9);26:1115-22. PMID 16919062
344: Schulte LH, Haji AA, May A. Phase dependent hypothalamic activation following trigeminal input in cluster headache. J Headache Pain 2020;21(1):30. PMID 32228453
345: Schurks M, Kurth T, Geissler I, Tessmann G, Diener HC, Rosskopf D. Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 2006;66:1917-9. PMID 16554494
346: Schurks M, Neumann FA, Kessler C, et al. MTHFR 677C>T polymorphism and cluster headache. Headache 2010;51:201-7. PMID 20946434
347: Seifert CL, Magon S, Staehle K, et al. A Case-Control Study on Cortical Thickness in Episodic Cluster Headache. Headache 2012;52(9):1362-68. PMID 22823926
348: Seijo-Martinez M, Castro del Rio M, Conde C, Brasa J, Vila O. Cluster-like headache: association with cervical syringomyelia and Arnold-Chiari malformation. Cephalalgia 2004;24(2):140-2. PMID 14728710
349: Sewell RA, Halpern JH, Pope HG. Response of cluster headache to psilocybin and LSD. Neurology 2006;66:1920-2. PMID 16801660
350: Shahbeigi S, Fereshtehnejad SM, Mohammadi N, et al. Epidemiology of headaches in Tehran urban area: a population-based cross-sectional study in district 8, year 2010. Neurol Sci 2013;34(7):1157-66. PMID 23010877
351: Silberstein SD. Pharmacological management of cluster headache. CNS Drugs 1994;2:199-207.
352: Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. First ed. Oxford: ISIS Medical Media, 1998.
353: Silberstein SD, Mechtler LL, Kudrow DB, et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 2016;56(8):1317-32. PMID 27593728
354: Silberstein SD, Niknam R, Rozen TD, Young WB. Cluster headache with aura. Neurology 2000;54:219-21. PMID 10636152
355: Silvestro M, Dovetto FM, Corvino V, et al. Enlarging the spectrum of cluster headache: extracranial autonomic involvement revealed by voice analysis. Headache 2021;61(9):1452-9. PMID 34618362
356: Silvestro M, Orologio I, Tartaglione L, et al. Infodemiology of cluster headache seasonality: a proof of concept by a Google Trends analysis. Headache 2023;63:89-93. PMID 36651518
357: Singh BN, Nademanee K. Use of calcium antagonists for cardiac arrhythmias. Am J Cardiol 1987;59:153B-62B. PMID 2433930
358: Singhal AB, Maas MB, Goldstein JN, et al. High-flow oxygen therapy for treatment of acute migraine: a randomized crossover trial. Cephalalgia 2017;37(8):730-6. PMID 27206964
359: Siow HC, Young WB, Peres MF, Rozen TD, Silberstein SD. Hemiplegic cluster. Headache 2002;42:136-9. PMID 12005289
360: Sjaastad O, Bakketeig LS. Cluster headache prevalence: Vaga study of headache epidemiology. Cephalalgia 2003;23:528-33. PMID 12950378
361: Sjostrand C, Giedratis V, Ekbom K, Waldenlind E, Hillert J. CACNA1A gene polymorphisms in cluster headache. Cephalalgia 2001;21:953-8. PMID 11843866
362: Sjostrand C, Modin H, Masterman T, Ekbom K, Waldenlind E, Hillert J. Analysis of nitric oxide synthase genes in cluster headache. Cephalalgia 2002;22:758-64. PMID 12421162
363: Sjostrand C, Waldenlind E, Ekbom K. A follow up study of 60 patients after an assumed first period of cluster headache. Cephalalgia 2000;20:653-7. PMID 11128823
364: Sluder G. The syndrome of sphenopalatine ganglion neurosis. Am J Med 1910;140:868-78.
365: Smart D, Jerman J. The physiology and pharmacology of the orexins. Pharmacol Ther 2002;94:51. PMID 12191593
366: Snoer A, Lund N, Beske R, Jensen R, Barloese M. Pre-attack signs and symptoms in cluster headache: characteristics and time profile. Cephalalgia 2018;38(6):1128-37. PMID 28816505
367: Snoer AH, Lund N, Jensen RH, Kristoffersen ES, Barloese M, Hansen JM. More precise phenotyping of cluster headache using prospective attack reports. Eur J Neurol 2019a;26(10):1303-e85. PMID 31059165
368: Snoer A, Vollesen ALH, Beske RP, et al. Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia 2019b;39(5):575-84. PMID 30854880
369: Snoer AH, Vollesen ALH, Beske RP, et al. S100B and NSE in cluster headache - evidence for glial cell activation? Headache 2020;60(8):1569-80. PMID 32548854
370: Soborg MK, Petersen AS, Lund N, Wandall-Holm MF, Jensen RH, Barloese M. Transition of cluster headache phenotype: an interview-based study. Cephalalgia 2023;43(1):3331024221128287. PMID 36587291
371: Soros P, Frese A, Husstedt IW, Evers S. Cluster headache after dental extraction: implications for the pathogenesis of cluster headache. Cephalalgia 2001;21(5):619-22. PMID 11472390
372: Sprenger T, Boecker H, Tolle TR, Bussone G, May A, Leone M. Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004;62:516-7. PMID 14872051
373: Sprenger T, Willoch F, Miederer M, et al. Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study. Neurology 2006;66:1108-10. PMID 16606930
374: Steinberg A, Wiklund NP, Brundin L, Remahl AI. Levels of nitric oxide metabolites in cerebrospinal fluid in cluster headache. Cephalalgia 2010;30:696-702. PMID 20511209
375: Stillman MJ. Testosterone replacement therapy for treatment refractory cluster headache. Headache 2006;46:925-33. PMID 16732838
376: Svensson D, Ekbom K, Pedersen NL, Traff H, Waldenlind E. A note on cluster headache in a population-based twin register. Cephalalgia 2003;23:376-80. PMID 12780768
377: Symonds CP. A particular variety of headache. Brain 1956;79:217-32. PMID 13364081
378: Takele GM, Tekle Haimanot R, Martelletti P. Prevalence and burden of primary headache in Akaki textile mill workers, Ethiopia. J Headache Pain 2008;9:119-28. PMID 18283416
379: Taub E, Argoff CE, Winterkorn JM, Milhorat TH. Resolution of chronic cluster headache after resection of a tentorial meningioma: case report. Neurosurgery 1995;37(2):319-21. PMID 7477785
380: Tay BA, Ngan Kee WD, Chung DC. Gabapentin for the treatment and prophylaxis of cluster headache. Reg Anesth Pain Med 2001;26:373-5. PMID 11464360
381: Tfelt-Hansen P, Paulson OB, Krabbe AE. Invasive adenoma of the pituitary gland and chronic migrainous neuralgia. A rare coincidence or a causal relationship. Cephalalgia 1982;2:25-8. PMID 7116439
382: Thomas AL. Periodic migrainous neuralgia associated with an arteriovenous malformation. Postgrad Med J 1975;51(597):460-2. PMID 1187500
383: Tonon C, Guttmann S, Volpini M, Naccarato S, Cortelli P, D'Alessandro R. Prevalence and incidence of cluster headache in the Republic of San Marino. Neurology 2002;58:1407-9. PMID 12011291
384: Torelli P, Cologno D, Cademartiri C, Manzoni GC. Primary and secondary chronic cluster headache: two separate entities. Cephalalgia 2000;20:826-9. PMID 11167912
385: Torelli P, Manzoni GC. What predicts evolution from episodic to chronic cluster headache. Curr Pain Headache Rep 2002;6:65-70. PMID 11749880
386: Tronvik E, Wienecke T, Monstad I, et al. Randomised trial on episodic cluster headache with an angiotensin II receptor blocker. Cephalalgia 2013;33(12):1026-34. PMID 23598371
387: Tsivgoulis G, Mantatzis M, Vadikolias K, et al. Internal carotid artery dissection presenting as new-onset cluster headache. Neurol Sci 2013;34(7):1251-2. PMID 23053833
388: Vail HH. Vidian neuralgia. Ann Otol Rhinol Laryngol 1932;41:837-56.
389: van der Vlist SH, Hummelink BJ, Westerga J, Boogerd W. Cluster-like headache and a cystic hypothalamic tumour as first presentation of sarcoidosis. Cephalalgia 2013;33(6):421-4. PMID 23405019
390: van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. Neurology 2003a;60:630-3. PMID 12601104
391: van Vliet JA, Eekers PJ, Haan J, Ferrari MD. Features involved in the diagnostic delay of cluster headache. J Neurol Neurosurg Psychiatry 2003b;74:1123-5. PMID 12876249
392: van Vliet JA, Eekers PJ, Haan J, Ferrari MD. Evaluating the IHS criteria for cluster headache--a comparison between patients meeting all criteria and patients failing one criterion. Cephalalgia 2006a;26:241-5. PMID 16472329
393: van Vliet JA, Favier I, Helmerhorst FM, Haan J, Ferrari MD. Cluster headache in women: relation with menstruation, use of oral contraceptives, pregnancy, and menopause. J Neurol Neurosurg Psychiatry 2006b;77:690-2. PMID 16407458
394: van Vliet JA, Vein AA, Ferrari MD, van Dijk JG. Cardiovascular autonomic function tests in cluster headache. Cephalalgia 2006c;26:329-31. PMID 16472341
395: Vingen JV, Pareja JA, Stovner LJ. Quantitative evaluation of photophobia and phonophobia in cluster headache. Cephalalgia 1998;18(5):250-6. PMID 9673803
396: Volcy M, Tepper SJ. Cluster-like headache secondary to idiopathic intracranial hypertension. Cephalalgia 2006;26(7):883-6. PMID 16776707
397: Vollesen ALH, Snoer A, Beske RP, et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol 2018;75(10):1187-97. PMID 29987329
398: Vollesen ALH, Snoer A, Chaudhry B, et al. The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache. Cephalalgia 2020;40(13):1474-88. PMID 32962406
399: Waldenlind E, Gustafsson SA, Ekbom K, Wetterberg L. Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987;50:207-13. PMID 3572435
400: Wang SJ, Lirng JF, Fuh JL, Chen JJ. Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J Neurol Neurosurg Psychiatry 2006;77:622-5. PMID 16614022
401: Wang Y, Zhou J, Fan X, et al. Classification and clinical features of headache patients: an outpatient clinic study from China. J Headache Pain 2011;12(5):561-7. PMID 21744226
402: Waung MW, Taylor A, Qualmann KJ, Burish MJ. Family history of cluster headache: a systematic review. JAMA Neurol 2020;77(7):887-96. PMID 32310255
403: Wei DY, Goadsby PJ. Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks. Cephalalgia 2021;41(8):913-33.** PMID 33615843
404: Wei DY, Goadsby PJ. Recent advances and updates in trigeminal autonomic cephalalgias. Semin Neurol 2022;42(4):474-8. PMID 36323300
405: Wei J, Robbins MS. Greater occipital nerve injection versus oral steroids for short term prophylaxis of cluster headache: a retrospective comparative study. Headache 2018;58(6):852-8. PMID 29782047
406: West P, Todman D. Chronic cluster headache associated with a vertebral artery aneurysm. Headache 1991;31:210-2. PMID 2050514
407: Wheeler SD, Carrazana EJ. Topiramate-treated cluster headache. Neurology 1999;53:234-6. PMID 10408573
408: Wilbrink LA, de Coo IF, Doesborg PGG, et al. Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial. Lancet Neurol 2021;20(7):515-25. PMID 34146510
409: Wilbrink LA, Louter MA, Teernstra OPM, et al. Allodynia in cluster headache. Pain 2017;158(6):1113-7. PMID 28267062
410: Winsvold BS, Harder AVE, Ran C, et al. Cluster headache genomewide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. Ann Neurol 2023;94(4):713-26. PMID 37486023
411: Wu JW, Chen ST, Wang YF, et al. Sphenopalatine ganglion volumetry in episodic cluster headache: from symptom laterality to cranial autonomic symptoms. J Headache Pain 2023;24(1):2. PMID 36597044
412: Xie Q, Huang Q, Wang J, Li N, Tan G, Zhou J. Clinical features of cluster headache: an outpatient clinic study from China. Pain Med 2013;14(6):802-7. PMID 23631424
413: Zidverc-Trajkovic J, Podgorac A, Radojicic A, Sternic N. Migraine-like accompanying features in patients with cluster headache. How important are they. Headache 2013;53(9):1464-9. PMID 23534887

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Peter J Goadsby MD PhD FRS

Dr. Goadsby of King’s College London received consulting fees from Abbvie, Aeon Biopharma, Amgen, Eli Lilly, Epalex, Lundbeck, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics, and Teva Neurosciences and a grant from Celegene.
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Editor

Shuu-Jiun Wang MD

Dr. Wang of National Yang-Ming University and Taipei Veterans General Hospital has no relevant financial relationships to disclose.
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Former Authors

Ninan Mathew MD

Patient Profile

Age range of presentation: 2 years to 65+ years
Sex preponderance: male>female, 4:1
Heredity: Generally no clear pattern although isolated families exist with an apparently autosomal dominant inheritance.
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Cluster headache

Associated Disorders

AVM in brain or scalp
C3 cervical root fibrosis
Calvarial, skull base, dural, and nasopharyngeal metastases
Cavernous carotid artery pseudoaneurysm
Chiari malformation
- Clivus epidermoid
- Dental extraction
- Herpes zoster ophthalmicus
- Hypothalamic tumors
- Idiopathic intracranial hypertension
- Impacted wisdom teeth
- Intracranial mass lesions
- Lateral medullary infarction
- Maxillary sinusitis
- Meningiomas
- Nasopharyngeal carcinoma
- Pain, headache, and oromandibular structures
- Pituitary adenoma
- Pituitary tumors
- Prepontine epidermoid tumor
- Prolactinoma
- Rhinosinus-related headache
- Spontaneous carotid and vertebral artery dissection
- SUNA
- SUNCT
- Syringomyelia
- Temporal arteritis
- Traumatic intracranial aneurysms
- Obstructive sleep apnea
- Paroxysmal hemicrania
- Trigeminal neuralgia
- Trigeminal neuralgia and other cranial neuralgias
- Unruptured cerebral aneurysm

Differential Diagnosis

Cluster migraine
Cluster tic syndrome
Dental and ENT disorders
Hemicrania continua
Hypnic headache
- Orbital myositis
- Paroxysmal hemicrania
- Raeder paratrigeminal neuralgia
- Short-lasting neuralgiform headache attacks with conjunctival injection and tearing
- Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms
- SUNA
- SUNCT
- TAC
- Temporal arteritis
- Tolosa-Hunt syndrome
- Trigeminal autonomic cephalalgias
- Trigeminal neuralgia
- Unruptured cerebral aneurysm

Also Relevant

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Dihydroergotamine
Epidemiology of headache
- Eye-related headache
- Headache associated with acute substance use or exposure
- Headache associated with hormonal fluctuations
- Headache associated with ischemic cerebrovascular disease
- Headache attributed to disorder of homeostasis
- Headache in children: overview and treatment approaches
- Hypnic headache
- Medication overuse headache
- Neuroimaging of headache
- Paroxysmal hemicrania
- Patent foramen ovale
- Primary stabbing headache
- Psychological factors and headache
- Rhinosinus-related headache
- Sleep and headaches
- Sumatriptan
- SUNCT syndrome
- Triptans
- Valproic acid

Cluster headache

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Table 1. Diagnostic Criteria for Cluster Headaches After ICHD-3

Table 2. Differential Diagnosis of Trigeminal Autonomic Cephalalgias

Confusing conditions

Table 3. Similar Conditions or Secondary Syndromes

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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