Skip to main content

Debate: Are cluster headache and migraine distinct headache disorders?

Abstract

Cluster headache and migraine are regarded as distinct primary headaches. While cluster headache and migraine differ in multiple aspects such as gender-related and headache specific features (e.g., attack duration and frequency), both show clinical similarities in trigger factors (e.g., alcohol) and treatment response (e.g., triptans). Here, we review the similarities and differences in anatomy and pathophysiology that underlie cluster headache and migraine, discuss whether cluster headache and migraine should indeed be considered as two distinct primary headaches, and propose recommendations for future studies.

Graphical Abstract

Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at https://www.youtube.com/watch?v=uUimmnDVTTE.

Peer Review reports

Introduction

In the International Classification of Headache Disorders (ICHD-3), cluster headache (CH) and migraine are categorized as primary headaches [1]. CH and migraine affect 0.1% and 15% of the general population, respectively [2, 3]. CH is more common in men (men to women ratio ~ 4.3:1) [4, 5], while migraine primarily affects women (women to men ratio ~ 3:1). The prevalence of migraine in individuals diagnosed with CH does not differ from the general population [5]. Important clinical differences between cluster headache and migraine headache include duration and frequency of attacks. A CH attack lasts between 15 and 180 minutes, and multiple attacks per day may occur, whereas the duration of a migraine attack is between 4 and 72 hours, and recurrence is defined as a headache within 22 hours of initial successful treatment of a migraine attack (2-hour headache response) [6]. Furthermore, CH attacks are often side-locked, occurring on one side most of the times [7], while migraine headache localization changes or may be bilateral [8]. Interestingly, both share some non-headache related symptoms such as photophobia or cranial autonomic symptoms (CAS), although these may be more pronounced in one or the other [9]. Occasionally, some patients report an intermediate phenotype that includes specific features of both primary headaches or has comorbid CH and migraine [10]. In such patients, the attack duration, the presence of restlessness vs. pain aggravated by physical activities, and a family history of CH may provide diagnostic clues to distinguish between CH and migraine [11]. These similarities and differences between CH and migraine give rise to a debate about whether CH and migraine should be considered part of the clinical headache continuum or whether they are two distinct primary headaches.

Phenotype

Clinical presentation of CH and migraine are shown in Tables 1 and 2. CH attacks are characterized by recurrent severe to very severe side-locked headaches associated with prominent ipsilateral CAS and/or agitation (Fig. 1). Attack frequency in CH ranges from one attack every other day to eight attacks a day [13, 14] with specific chronobiological features, mainly circadian (most frequently nocturnal) and circannual rhythms. In episodic CH, the attacks occur in a series of daily attacks lasting weeks or months (cluster bout) followed by a complete remission for months or years (Fig. 2) [14]. The age at onset of CH ranged from 10–68 years of age [16], with a peak between 20–30 years of age for both sexes (observed in ~40% of patients) [14]. Onset declines between 31–40 years of age (observed in 16% of patients) and between 41–50 years of age (observed in 10% of patients) [14].

Table 1 ICHD-3 Diagnostic criteria for cluster headache
Table 2 ICHD-3 Diagnostic Criteria for Migraine
Fig. 1
figure 1

Clinical manifestation. Migraine is known for prodromal symptoms such as yawning, mood and cognitive changes, and neck pain which precede migraine headache for up to 2–3 days. Interestingly, Cluster headache (CH) patients also report prodromal symptoms which differ from those of migraine in their duration (up to one hour before CH attack). Eventually, migraine aura usually precedes the migraine headache, while the aura in CH patient is caused by a comorbid migraine with aura [12]

Fig. 2
figure 2

Chronobiologic rhythms. Cluster headache (CH) shows specific chronobiological features, mainly circadian (most frequently nocturnal) and circannual rhythms. In episodic CH, the attacks appear in a series of daily attacks lasting for weeks or months (cluster bout) followed by a complete remission for months or years. Migraine attacks rarely affect sleep and frequently occur during the day. Although migraine patients experience periodicity in attack frequency and severity [15], the periodicity of migraine attacks is not prominent compared to CH attacks

Migraine attacks are characterized by recurrent unilateral moderate to severe pulsating headaches, aggravated by routine physical activity. Strictly unilateral (side-locked) headache are reported in approximately 26% of migraine patients [17], and up to 40% of the individuals with migraine reported bilateral headache [18]. Migraine is a life span disease with an age-dependent change. The prevalence of migraine increases with age and peaks at 35–39 years of age, followed by a decline [19]. These changes may include transformation from episodic to chronic migraine or even a disappearance of some or all migraine symptoms [20]. Although, seasonal variation of migraine attacks is less prominent and migraine attacks are more equally distributed compared to CH attacks (Fig. 2), some patients experience periodicity and report increased frequency of attacks at certain times of the year [15]. Migraine attacks rarely affect sleep and frequently occur during the day (Figs. 2 and 3). CH and migraine may coexist in the same patient. Cross-sectional cohort studies reported comorbid migraine in 10–16.7% of patients with CH [33,34,35]. Notably, the proportion is similar to the prevalence of migraine in the general population [3]. Comorbid CH in migraine cohorts has yet to be investigated. This partially reflects the relatively low prevalence of CH in the general population [2]. Whether the comorbidity suggests a shared disease mechanism or a co-occurrence by chance requires further investigation, especially in longitudinal studies.

Fig. 3
figure 3

Trigeminovascular system (TVS). Generation of Cluster headache (CH) involves the trigeminocervical complex (TCC), the parasympathetic nerve fibers (trigeminal autonomic reflex (TAR)), and the hypothalamus [21,22,23,24,25,26,27,28,29]. Peripheral fibers of neurons in the trigeminal ganglions (TG) transmit nociceptive information from dura mater and cranial vessels to the TCC in the brainstem. Fibers from the TCC project to thalamic neurons (via the trigemino-thalamic tract) and to hypothalamic neurons (via the trigemino-hypothalamic tract). Neurons within the TCC are connected to parasympathetic neurons in the superior salivatory nucleus, and the activation of the parasympathetic system by the trigeminal neurons comprises the TAR. The parasympathetic fibers from the superior salivatory nucleus pass through the facial nerve and the sphenopalatine ganglion (SPG) on the way to the periphery. Release of neuropeptides upon activation of the parasympathetic system causes autonomic symptoms such as cephalic vasodilation, conjunctival injection, lacrimation and rhinorrhea. Clinical experience indicates involvement of TAR in CH more than migraine. This notion is further strengthened by the finding that low frequency SPG stimulation induced CH attacks with autonomic features, which could subsequently be treated by high frequency SPG stimulation [30]. Low frequency stimulation of the SPG did not induce migraine attacks or autonomic symptoms in migraine patients. These data suggest that increased parasympathetic outflow by (SPG) neurostimulator does not initiate migraine attacks [31]. However, a recent study demonstrated that low frequency SPG stimulation induced autonomic features but no CH attacks [32]. The clinical manifestation of CH attacks, including circadian rhythm dependence, relapsing– remitting presentations and ipsilateral cranial autonomic symptoms indicate hypothalamic involvement. While the anterior hypothalamus might contribute to the circadian rhythm of CH attacks, the lateral and posterior part might generate the restlessness experienced by CH patients during the attack. Neuroimaging investigations report a role of the hypothalamus during the prodrome symptoms and dorsolateral pons during the ictal phase of attacks in individuals with migraine patients. CH and migraine seem to share anatomical structure with distinct biology

Ipsilateral CAS with an average of four symptoms [14] have been reported in >90% of patients with CH (Table 3) [48]. Migraine patients may also experience CAS, but studies reported a wide range of prevalence 30–75% [49,50,51]. The average of CAS during migraine attack is 2 symptoms/attacks [45], which is equivalent to half of what a CH patient experiences, even though it has never been investigated head-to-head. Photophobia defined as enhanced sensitivity to light is one of the most typical associated symptoms of migraine reported in ≥80% of migraine patients [42], Of note, 80% of patients with CH report photophobia during their attacks (Table 3) [43, 52]. Visual allodynia defined as enhanced sensitivity to light and patterns was recently investigated in CH. Interestingly, CH patients mostly report unilateral visual allodynia that is ipsilateral to the side of the ictal pain [53, 54]. Cutaneous allodynia is a common feature accompanying migraine attacks [55] and is considered a clinical marker of central sensitization [38], and a risk factor for migraine chronification [38] but not associated with chronic CH [41]. Interestingly, 36% of patients with CH report allodynia during attacks [41]. Female gender, young age at onset, lifetime depression, comorbid migraine, and recent attacks were independent risk factors for allodynia. The high prevalence of cutaneous allodynia with similar risk factors for allodynia as found for migraine suggests that central sensitization, as with migraine, also occurs in CH [41]. However, it remains to be seen whether the presence of allodynia in CH has a predictive value for treatment response. An important clinical difference that distinguishes CH from migraine is the restlessness, which causes patients to wander during attacks [46, 47]. While light physical activity exacerbates migraine headache, and migraine patients usually lie down during attacks (Table 3) [1].

Table 3 Clinical presentation. Comparison of clinical presentation between cluster headache and migraine

Migraine patients may experience prodromal symptoms such as yawning, changes in mood and difficulty concentrating, as well as neck pain which precede migraine headache by up to 2–3 days (Fig. 1) [56]. In contrast, similar prodromal symptoms in CH precede attacks by up to one hour (Fig. 1) [36, 57]. In the case of aura, migraine aura usually precedes the migraine headache, while the aura in CH patient is often caused by a comorbid migraine with aura (Fig. 2) [12]. Thus, the clinical manifestations of both primary headaches overlap to some extent; however, the striking circannual and circadian periodicity, duration of attacks and some associated symptoms are clearly different (Fig. 2).

Disease Mechanisms

Genetics

The risk for first-degree relatives of CH patients to develop CH is estimated to be 5–18 times higher than that of the general population [58], while the risk for first-degree relatives of migraine patients to develop migraine is estimated to be 1.9- (migraine without aura) and 3.8-fold increased (migraine with aura), compared to the risk in the general population [59]. However, although we cannot exclude that some patients might inherit CH in a mendelian fashion, multifactorial inheritance, as is almost always also the case in migraine, seems likely [60, 61]. For a long time, while we increasingly understood the genetic architecture of migraine, the genetic basis of CH remained a mystery. Whether there is a genetic overlap between them remained a conundrum.

The latest genome-wide association study (GWAS) of migraine found 123 loci, of which 86 were previously unknown [62]. Here, 102,084 migraine cases and 771,257 controls were analyzed. Two recent GWAS studies independently identified the first four replicating genomic loci associated with CH (even though less than 1500 CH patients were included per study) [63, 64]. Interestingly, one of the associated loci, located on chromosome 6, which covers both FHL5 and UFL1, overlaps with a previous known migraine locus. Moreover, the association had the same effect direction for both CH and migraine. Notedly, the effect sizes were higher for CH (OR≈1.30) than for migraine (OR≈1.09) for this locus [63, 64]. The larger effect size for CH makes it unlikely that misclassification and comorbid migraine causes this identified association and suggests that this locus has a greater effect on risk of developing CH than migraine. The effect size might also be influenced by the CH populations, that were very homogenous and had validated diagnosis according to the ICHD-criteria. To date, no other migraine loci have been identified to associate with CH (36 other loci from the migraine 2016 meta-analyses were tested) [63, 64]. So, while CH and migraine might partly share their genetic architecture, they probably also have distinct genetic components. This may suggest both partly shared and partly distinct involved biological mechanisms.

Pathophysiology

The trigeminovascular system (TVS) is the anatomical and physiological substrate of CH [7] and migraine [65] (Fig. 3). Activation of the TVS is associated with release of various vasoactive neuropeptides, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide (VIP). To explore signaling pathways within the TVS, several pharmacological compounds were used to induce CH attacks and migraine attacks including histamine, glyceryl trinitrate (GTN), CGRP, PACAP38 and VIP [66,67,68].

Pharmacological triggers for migraine attacks are effective triggers for CH attacks (Table 4). In randomized placebo-controlled clinical trials (RCT), GTN and CGRP induced CH attacks [69, 70]. One RCT investigated PACAP38 and VIP head-to-head in the same CH patients [71]. Interestingly, CH attacks are triggered faster (~30 min, range 10–90 min) compared to migraine attacks (~5 hours, 2–11 hours) (Table 4). Additionally, the induction rate of CH attack is highly dependent on the disease phase: episodic in-bout and chronic versus out-of-bout (remission). Intravenous infusion of CGRP induced CH in episodic and chronic CH patients but patients in remission phase reported no attacks. Interestingly, CH attacks in chronic patients are less likely to be triggered, while the potency of CGRP as a migraine inductor is increased in chronic migraine patients with ongoing headache [72]. These observations suggest that CH and migraine share anatomical structures and pathophysiological mechanisms but differ in signaling cascades leading to attack initiation. Notably, participants diagnosed with other types of headaches including persistent post-traumatic headache are also hypersensitive to CGRP [73], indicating that CGRP has an integral role in the pathogenesis of headache in general and not specific for CH and migraine.

Table 4 Provocation studies. Cluster headache and migraine have several pharmacological triggers in common but different methodological approach have been applied in attack induction

Gender-related etiology of CH and migraine suggests that sex hormones are affected in both disorders. It is reported that male patients with CH exhibited decreased levels of testosterone [74], and male patients with migraine exhibited increased levels of estradiol and showed a clinical evidence of relative androgen deficiency compared to controls [75]. Yet, the influence of sex hormone is complex, and more insight is needed to make conclusive comments on the similarities and differences.

Prodromal symptoms and imaging

Longitudinal human studies showed a significant hypothalamic activation up to 48 hours before migraine headache [76, 77]. Although no prodromal symptoms were recorded, these studies concluded that hypothalamus is linked to prodromal symptoms preceding the ictal phase of migraine attacks [76, 77]. Imaging studies showed that other brain regions were activated, such as the midbrain tegmental area and periaqueductal grey [78]. To date, no functional imaging studies have investigated CH patients during prodromal symptoms. The hypothalamus is activated during the ictal period of CH attacks [79]. A recent fMRI study revealed an activation of the posterior hypothalamus by trigeminonociceptive stimuli in CH patients during remission, suggesting an important role of the hypothalamus, even outside the headache attacks [80]. Interestingly, the anterior hypothalamus is activated in patients with chronic migraine [81] and chronic CH [82]. Given that the hypothalamus modulates chronological rhythm [83] and its specific subnuclei may explain prodromal symptoms [83], it would be plausible to suggest the hypothalamus may also play an important role in the genesis of migraine and CH attacks.

Treatment

Management of CH and migraine involve acute and preventive treatments. Triptans are serotonin agonists which target 5-HT1B and 5HT1D receptors [84]. Since the pharmacodynamics of triptans are rather specific and do not involve the antinociceptive activity against noxious stimuli, triptans are ineffective in non-cephalic pain conditions [85]. RCTs showed that triptans are effective as acute therapies for migraine [86] and CH attacks [87] (Table 5). Oxygen therapy (inhalation of 100% oxygen through a face mask with a flow of 12–15 L/min) is widely used to relieve acute pain during CH attacks [21]. The exact underlying mechanism for this effect is uncertain, and several explanations have been proposed, including inhibition of the trigeminoautonomic reflex (TAR), modulation of neurotransmitters, and cerebral vasoconstriction [88,89,90]. To date, no RCT has assessed the efficacy of oxygen therapy in migraine patients.

Table 5 Treatment. Comparison of treatment responses between cluster headache and migraine

The first-line CH preventive treatment verapamil [91] has only slight efficacy in migraine prevention [92]. Candesartan, an angiotensin II receptor antagonist, showed effectiveness in migraine prevention [93] but failed to prevent CH [94]. Inhibition of the parasympathetic outflow by sphenopalatine ganglion (SPG) stimulation showed dual beneficial effects, acute pain relief and attack prevention in CH [22]. In contrast, migraine patients did not report any meaningful response after SPG stimulation [95]. Non-invasive vagus nerve stimulation (nVNS) showed significant efficacy in aborting migraine attacks [96] and attacks in episodic CH, but not attacks in chronic CH [97].

Anti-CGRP monoclonal antibodies (CGRP-mAb) including galcanezumab and fremanezumab are novel mechanism-based therapies developed for migraine prevention [98]. Four RCTs assessed the safety and efficacy of CGRP-mAb to prevent CH. In episodic CH, galcanezumab reduced CH attacks by 3.5 per week (95% CI: 0.2–6.7, p = 0.04) [99]. In chronic CH, galcanezumab did not meet its primary and key secondary endpoints [100]. Clinical trials with fremanezumab (NCT02945046 with episodic and chronic CH participants; and NCT02964338 with chronic CH participants) were discontinued due to the negative results of the mid-term futility analysis. These conflicting findings highlight the irregularity and unpredictability of cluster periods across participants and the spontaneous remission as part of the natural history of episodic CH [101]. Interestingly, treatment efficacy differs greatly between episodic and chronic CH patients. Patients with chronic CH were less likely to respond to intranasal zolmitriptan [102] or oxygen therapy [103]. Verapamil is almost 50% less likely to be effective in patients with chronic CH compared to those with episodic CH [104]. Additionally, none of the new treatment options, such as CGRP-mAb or nVNS, have been shown to be effective in chronic CH [97, 100], despite efficacy in patients with episodic CH [97, 99]. One explanation for these observations is that chronic CH patients have a low threshold and are thus more susceptible to recurrent attacks. Another possible explanation would be a different neurobiology. For example, chronic CH patients, in addition to a circadian rhythm, have an additional ultradian rhythm – a period ≤24 h and averaged 4.8 h in one study [105], and serum CGRP levels were lower in chronic patients than episodic patients [106]. Taken together, CH and migraine share clinical efficacy to treatment options (Table 5) with a specific mechanism of action.

Lessons Learned and Future Directions

CH and migraine appear to have a strong genetic component. The latest CH GWASs indicated that they share at least one genetic locus. Increasing sample size (mainly for the CH cohorts currently available for analyses) and meta-analyses of the genetic data available will further elucidate shared and distinct genetic components of the disorders. Despite the abundance of shared clinical features between CH and migraine, none of the headache features are specific to any headache diagnosis. For example, photophobia is not restricted to CH or migraine [107]. Patients with secondary headaches including post-traumatic headache and headache attributed to intracranial infection (e.g. meningitis) may report photophobia and other clinical manifestation that mimic primary headaches [108, 109]. Thus, none of the clinical features are diagnosis-specific and possibly simply reflects the activation of the trigeminal pain pathway. The presence or absence of certain associated symptoms may reflect the degree of activation: e.g., CAS might only accompany severe headaches. The most striking characteristic of CH is the short attack duration. Regardless of the severity and intensity of the attack, the attack stops spontaneously within 180 minutes. The mechanism of how cluster and migraine attacks stop spontaneously remains unknown. In discussing the structures and molecules involved in CH and migraine, numerous questions remained to be answered: 1) molecular pathways responsible for genesis of attacks; 2) factors modulating susceptibility to attacks; 3) the precise mechanisms and order of events behind the initiation of attacks; 4) molecular pathways underlying attack termination. Pharmacological provocation studies in both CH and migraine provided valuable information on molecular signaling pathways. Recent studies that targeted the downstream signaling pathway in the vascular smooth muscles are intriguing: the opening of ATP-sensitive potassium (KATP) channels [110] or high-conductance (big) calcium-activated potassium channels (BKCa) channels [111] served as highly effective migraine attack triggers (95–100%). Clinical trials in patients with CH are still ongoing (NCT05093582), and such studies are critical in deciphering the genesis of CH attacks. Functional imaging studies are known to be influenced by the study site, study design, and even analytical methods [112]. Studies using resting-state fMRI are highly depend on participants’ alertness and are rarely reproducible [113]. To reduce inter-study and even inter-session differences, headache-to-headache comparison between CH and migraine will be necessary, and these studies are still lacking. Furthermore, functional imaging studies investigating patients with CH are difficult to conduct because patients usually have restlessness during their attacks.

Although patients with CH and migraine share several specific treatment options, the mechanism or the site of action remains largely uncertain. Another critical question is whether drug response should be used to assist diagnose and classify headache disorders? Response to the drug has only been adopted as a diagnostic criterion in paroxysmal hemicrania and hemicrania continua. In addition, for any given medication, there are always clinical responders vs. clinical non-responders. The diverse response to a specific medication suggests that the clinical cohort, e.g., migraine patients, can still be divided into those with distinct molecular mechanisms (and hence different response to specific treatment).

Conclusions

CH and migraine share some clinical features, including non-headache (pre) ictal features such as prodromal features, (inter) ictal visual hypersensitivity, ictal allodynia and cranial autonomic features. Demographics, genetics and chronological patterns suggest partly overlap, but also important differences in pathophysiological mechanisms. Common pharmacological triggers suggest shared anatomical and pathophysiological substrate, but as CH attacks are triggered faster compared to migraine attacks, signaling cascades leading to attack initiation might differ. More studies are needed to improve understanding of the disease mechanism of CH and migraine. It is also crucial to discover potential biomarkers, with which we may better categorize the disease entity and help identify the susceptible group for specific treatment options.

References

  1. Headache Classification Committee of the International Headache Society (IHS) (2018) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38:1–211. https://doi.org/10.1177/0333102417738202

    Article  Google Scholar 

  2. Fischera M, Marziniak M, Gralow I, Evers S (2008) The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia 28:614–618. https://doi.org/10.1111/j.1468-2982.2008.01592.x

    Article  PubMed  CAS  Google Scholar 

  3. Stovner LJ, Hagen K, Linde M, Steiner TJ (2022) The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 23:34. https://doi.org/10.1186/s10194-022-01402-2

    Article  PubMed  PubMed Central  Google Scholar 

  4. Manzoni G (1998) Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia 18:138–142. https://doi.org/10.1046/j.1468-2982.1998.1803138.x

    Article  PubMed  CAS  Google Scholar 

  5. Lund N, Barloese M, Petersen A et al (2017) Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology 88:1069–1076. https://doi.org/10.1212/WNL.0000000000003715

    Article  PubMed  Google Scholar 

  6. Diener H-C, Tassorelli C, Dodick DW et al (2019) Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: Fourth edition. Cephalalgia 39:687–710. https://doi.org/10.1177/0333102419828967

    Article  PubMed  PubMed Central  Google Scholar 

  7. May A, Schwedt TJ, Magis D et al (2018) Cluster headache. Nat Rev Dis Primer 4:18006. https://doi.org/10.1038/nrdp.2018.6

    Article  Google Scholar 

  8. Eigenbrodt AK, Ashina H, Khan S et al (2021) Diagnosis and management of migraine in ten steps. Nat Rev Neurol 17:501–514. https://doi.org/10.1038/s41582-021-00509-5

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vollesen AL, Benemei S, Cortese F et al (2018) Migraine and cluster headache - the common link. J Headache Pain 19:89. https://doi.org/10.1186/s10194-018-0909-4

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nelson RF (1970) Cluster migraine--an unrecognized common entity. Can Med Assoc J 103:1026–1030

    PubMed  PubMed Central  CAS  Google Scholar 

  11. Sjöstrand C, Russell M, Ekbom K et al (2005) Familial cluster headache. is atypical cluster headache in family members part of the clinical spectrum? Cephalalgia 25:1068–1077. https://doi.org/10.1111/j.1468-2982.2005.00964.x

    Article  PubMed  Google Scholar 

  12. Peng K-P, Schellong M, May A (2022) Aura in trigeminal autonomic cephalalgia is probably mediated by comorbid migraine with aura. Cephalalgia 42:31–36. https://doi.org/10.1177/03331024211030499

    Article  PubMed  Google Scholar 

  13. Barloese MCJ (2015) Neurobiology and sleep disorders in cluster headache. J Headache Pain 16:562. https://doi.org/10.1186/s10194-015-0562-0

    Article  PubMed  Google Scholar 

  14. Rozen TD, Fishman RS (2012) Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 52:99–113. https://doi.org/10.1111/j.1526-4610.2011.02028.x

    Article  PubMed  Google Scholar 

  15. Poulsen AH, Younis S, Thuraiaiyah J, Ashina M (2021) The chronobiology of migraine: a systematic review. J Headache Pain 22:76. https://doi.org/10.1186/s10194-021-01276-w

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ekbom K, Svensson DA, Träff H, Waldenlind E (2002) Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia 22:94–100. https://doi.org/10.1046/j.1468-2982.2002.00318.x

    Article  PubMed  CAS  Google Scholar 

  17. Da Silva AN, Tepper SJ, Evans RW (2012) Side-locked and side shifting primary headaches. Headache 52:1178–1183. https://doi.org/10.1111/j.1526-4610.2012.02196.x

    Article  PubMed  Google Scholar 

  18. Rasmussen BK, Olesen J (1992) Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12:221–228; discussion 186. https://doi.org/10.1046/j.1468-2982.1992.1204221.x

    Article  PubMed  CAS  Google Scholar 

  19. Ashina M, Katsarava Z, Do TP et al (2021) Migraine: epidemiology and systems of care. Lancet 397:1485–1495. https://doi.org/10.1016/S0140-6736(20)32160-7

    Article  PubMed  Google Scholar 

  20. Andreou AP, Edvinsson L (2019) Mechanisms of migraine as a chronic evolutive condition. J Headache Pain 20:117. https://doi.org/10.1186/s10194-019-1066-0

    Article  PubMed  PubMed Central  Google Scholar 

  21. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ (2009) Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache 49:1131–1143. https://doi.org/10.1111/j.1526-4610.2009.01501.x

    Article  PubMed  Google Scholar 

  22. Schoenen J, Jensen RH, Lantéri-Minet M et al (2013) Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: A randomized, sham-controlled study. Cephalalgia 33:816–830. https://doi.org/10.1177/0333102412473667

    Article  PubMed  PubMed Central  Google Scholar 

  23. Akerman S, Holland PR, Summ O et al (2012) A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain 135:3664–3675. https://doi.org/10.1093/brain/aws249

    Article  PubMed  Google Scholar 

  24. Robert C, Bourgeais L, Arreto C-D et al (2013) Paraventricular Hypothalamic Regulation of Trigeminovascular Mechanisms Involved in Headaches. J Neurosci 33:8827–8840. https://doi.org/10.1523/JNEUROSCI.0439-13.2013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. May A, Goadsby P (2016) The enigma of the interconnection of trigeminal pain and cranial autonomic symptoms. Cephalalgia 36:727–729. https://doi.org/10.1177/0333102415611410

    Article  PubMed  Google Scholar 

  26. May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19:115–127. https://doi.org/10.1097/00004647-199902000-00001

    Article  PubMed  CAS  Google Scholar 

  27. Pietzsch JB, Garner A, Gaul C, May A (2015) Cost-effectiveness of stimulation of the sphenopalatine ganglion (SPG) for the treatment of chronic cluster headache: a model-based analysis based on the Pathway CH-1 study. J Headache Pain 16:530. https://doi.org/10.1186/s10194-015-0530-8

    Article  PubMed  CAS  Google Scholar 

  28. Ansarinia M, Rezai A, Tepper SJ et al (2010) Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches. Headache 50:1164–1174. https://doi.org/10.1111/j.1526-4610.2010.01661.x

    Article  PubMed  Google Scholar 

  29. Jürgens TP, Barloese M, May A et al (2017) Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 37:423–434. https://doi.org/10.1177/0333102416649092

    Article  PubMed  Google Scholar 

  30. Schytz HW, Barløse M, Guo S et al (2013) Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans. Cephalalgia 33:831–841. https://doi.org/10.1177/0333102413476370

    Article  PubMed  Google Scholar 

  31. Guo S, Falkenberg K, Schytz HW et al (2020) Low frequency activation of the sphenopalatine ganglion does not induce migraine-like attacks in migraine patients. Cephalalgia 40:966–977. https://doi.org/10.1177/0333102420921156

    Article  PubMed  Google Scholar 

  32. Guo S, Petersen AS, Schytz HW et al (2018) Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks. Cephalalgia 38:1418–1428. https://doi.org/10.1177/0333102417738250

    Article  PubMed  Google Scholar 

  33. Taga A, Russo M, Manzoni GC, Torelli P (2017) Cluster headache with accompanying migraine-like features: a possible clinical phenotype. Headache 57:290–297. https://doi.org/10.1111/head.12971

    Article  PubMed  Google Scholar 

  34. D’Amico D, Centonze V, Grazzi L et al (1997) Coexistence of migraine and cluster headache: report of 10 cases and possible pathogenetic implications. Headache 37:21–25. https://doi.org/10.1046/j.1526-4610.1997.3701021.x

    Article  PubMed  Google Scholar 

  35. Steinberg A, Fourier C, Ran C et al (2018) Cluster headache - clinical pattern and a new severity scale in a Swedish cohort. Cephalalgia 38:1286–1295. https://doi.org/10.1177/0333102417731773

    Article  PubMed  Google Scholar 

  36. Snoer A, Lund N, Beske R et al (2018) Pre-attack signs and symptoms in cluster headache: Characteristics and time profile. Cephalalgia 38:1128–1137. https://doi.org/10.1177/0333102417726498

    Article  PubMed  Google Scholar 

  37. Giffin NJ, Ruggiero L, Lipton RB et al (2003) Premonitory symptoms in migraine: an electronic diary study. Neurology 60:935–940

    Article  PubMed  CAS  Google Scholar 

  38. Louter MA, Bosker JE, van Oosterhout WPJ et al (2013) Cutaneous allodynia as a predictor of migraine chronification. Brain 136:3489–3496. https://doi.org/10.1093/brain/awt251

    Article  PubMed  Google Scholar 

  39. Bigal ME, Ashina S, Burstein R et al (2008) Prevalence and characteristics of allodynia in headache sufferers: a population study. Neurology 70:1525–1533. https://doi.org/10.1212/01.wnl.0000310645.31020.b1

    Article  PubMed  CAS  Google Scholar 

  40. Lipton RB, Bigal ME, Ashina S et al (2008) Cutaneous allodynia in the migraine population. Ann Neurol 63:148–158. https://doi.org/10.1002/ana.21211

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wilbrink LA, Louter MA, Teernstra OPM et al (2017) Allodynia in cluster headache. Pain 158:1113–1117. https://doi.org/10.1097/j.pain.0000000000000891

    Article  PubMed  Google Scholar 

  42. Choi J-Y, Oh K, Kim B-J et al (2009) Usefulness of a photophobia questionnaire in patients with migraine. Cephalalgia 29:953–959. https://doi.org/10.1111/j.1468-2982.2008.01822.x

    Article  PubMed  Google Scholar 

  43. Vingen JV, Pareja J, Stovner L (1998) Quantitative evaluation of photophobia and phonophobia in cluster headache. Cephalalgia 18:250–256. https://doi.org/10.1046/j.1468-2982.1998.1805250.x

    Article  PubMed  CAS  Google Scholar 

  44. Vingen JV, Pareja J, Støren O et al (1998) Phonophobia in Migraine. Cephalalgia 18:243–249. https://doi.org/10.1111/j.1468-2982.1998.1805243.x

    Article  PubMed  CAS  Google Scholar 

  45. Karsan N, Nagaraj K, Goadsby PJ (2022) Cranial autonomic symptoms: prevalence, phenotype and laterality in migraine and two potentially new symptoms. J Headache Pain 23:18. https://doi.org/10.1186/s10194-022-01389-w

    Article  PubMed  PubMed Central  Google Scholar 

  46. Imai N, Yagi N, Kuroda R et al (2011) Clinical profile of cluster headaches in Japan: low prevalence of chronic cluster headache, and uncoupling of sense and behaviour of restlessness. Cephalalgia 31:628–633. https://doi.org/10.1177/0333102410391486

    Article  PubMed  Google Scholar 

  47. Torelli P, Manzoni GC (2003) Pain and behaviour in cluster headache. A prospective study and review of the literature. Funct Neurol 18:205–210

    PubMed  Google Scholar 

  48. Chu MK, Kim B-S, Chung P-W et al (2021) Clinical features of cluster headache without cranial autonomic symptoms: results from a prospective multicentre study. Sci Rep 11:6916. https://doi.org/10.1038/s41598-021-86408-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Barbanti P, Fabbrini G, Pesare M et al (2002) Unilateral Cranial Autonomic Symptoms in Migraine. Cephalalgia 22:256–259. https://doi.org/10.1046/j.1468-2982.2002.00358.x

    Article  PubMed  CAS  Google Scholar 

  50. Obermann M, Yoon M-S, Dommes P et al (2007) Prevalence of trigeminal autonomic symptoms in migraine: a population-based study. Cephalalgia 27:504–509. https://doi.org/10.1111/j.1468-2982.2007.01316.x

    Article  PubMed  CAS  Google Scholar 

  51. Gupta R, Bhatia MS (2007) A report of cranial autonomic symptoms in migraineurs. Cephalalgia 27:22–28. https://doi.org/10.1111/j.1468-2982.2006.01237.x

    Article  PubMed  CAS  Google Scholar 

  52. Rozen TD (2001) Cluster headache in women: clinical characteristics and comparison with cluster headache in men. J Neurol Neurosurg Psychiatry 70:613–617. https://doi.org/10.1136/jnnp.70.5.613

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Perenboom MJL, Zamanipoor Najafabadi AH, Zielman R et al (2018) Quantifying visual allodynia across migraine subtypes: the Leiden Visual Sensitivity Scale. Pain 159:2375–2382. https://doi.org/10.1097/j.pain.0000000000001343

    Article  PubMed  PubMed Central  Google Scholar 

  54. Brandt RB, Cnossen VM, Doesborg PG et al (2022) Unilateral increased visual sensitivity in cluster headache: a cross-sectional study. Cephalalgia 42:722–729. https://doi.org/10.1177/03331024221077664

    Article  PubMed  Google Scholar 

  55. Burstein R, Yarnitsky D, Goor-Aryeh I et al (2000) An association between migraine and cutaneous allodynia. Ann Neurol 47:614–624

    Article  PubMed  CAS  Google Scholar 

  56. Blau JN (1980) Migraine prodromes separated from the aura: complete migraine. BMJ 281:658–660. https://doi.org/10.1136/bmj.281.6241.658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Blau J, Engel H (1998) Premonitory and Prodromal Symptoms in Cluster Headache. Cephalalgia 18:91–93. https://doi.org/10.1046/j.1468-2982.1998.1802091.x

    Article  PubMed  CAS  Google Scholar 

  58. Bjørn Russell M (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3:279–283. https://doi.org/10.1016/S1474-4422(04)00735-5

    Article  Google Scholar 

  59. Russell M (1997) Genetic epidemiology of migraine and cluster headache. Cephalalgia 17:683–701. https://doi.org/10.1046/j.1468-2982.1997.1706683.x

    Article  PubMed  CAS  Google Scholar 

  60. Polderman TJC, Benyamin B, de Leeuw CA et al (2015) Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 47:702–709. https://doi.org/10.1038/ng.3285

    Article  PubMed  CAS  Google Scholar 

  61. Russell MB, Andersson PG, Thomsen LL, Iselius L (1995) Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J Med Genet 32:954–956. https://doi.org/10.1136/jmg.32.12.954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Hautakangas H, Winsvold BS, Ruotsalainen SE et al (2022) Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet 54:152–160. https://doi.org/10.1038/s41588-021-00990-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Harder AVE, Winsvold BS, Noordam R et al (2021) Genetic susceptibility loci in genomewide association study of cluster headache. Ann Neurol 90:203–216. https://doi.org/10.1002/ana.26146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. O’Connor E, Fourier C, Ran C et al (2021) Genome-wide association study identifies risk loci for cluster headache. Ann Neurol 90:193–202. https://doi.org/10.1002/ana.26150

    Article  PubMed  CAS  Google Scholar 

  65. Ashina M (2020) Migraine. N Engl J Med 383:1866–1876. https://doi.org/10.1056/NEJMra1915327

    Article  PubMed  CAS  Google Scholar 

  66. Ashina M, Terwindt GM, Al-Karagholi MA-M et al (2021) Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 397:1496–1504. https://doi.org/10.1016/S0140-6736(20)32162-0

    Article  PubMed  CAS  Google Scholar 

  67. Hoffmann J, May A (2018) Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol 17:75–83. https://doi.org/10.1016/S1474-4422(17)30405-2

    Article  PubMed  Google Scholar 

  68. May A (2005) Cluster headache: pathogenesis, diagnosis, and management. Lancet 366:843–855. https://doi.org/10.1016/S0140-6736(05)67217-0

    Article  PubMed  Google Scholar 

  69. Vollesen ALH, Snoer A, Beske RP et al (2018) Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol 75:1187. https://doi.org/10.1001/jamaneurol.2018.1675

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wei DY, Goadsby PJ (2021) Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks. Cephalalgia 41:913–933. https://doi.org/10.1177/0333102421989617

    Article  PubMed  PubMed Central  Google Scholar 

  71. Vollesen ALH, Snoer A, Chaudhry B et al (2020) The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache. Cephalalgia 40:1474–1488. https://doi.org/10.1177/0333102420940689

    Article  PubMed  Google Scholar 

  72. Iljazi A, Ashina H, Zhuang ZA et al (2021) Hypersensitivity to calcitonin gene-related peptide in chronic migraine. Cephalalgia 41:701–710. https://doi.org/10.1177/0333102420981666

    Article  PubMed  Google Scholar 

  73. Ashina H, Iljazi A, Al-Khazali HM et al (2020) Hypersensitivity to calcitonin gene-related peptide in post-traumatic headache. Ann Neurol 88:1220–1228. https://doi.org/10.1002/ana.25915

    Article  PubMed  CAS  Google Scholar 

  74. Stillman M, Spears R (2008) Endocrinology of cluster headache: potential for therapeutic manipulation. Curr Pain Headache Rep 12:138–144. https://doi.org/10.1007/s11916-008-0026-1

    Article  PubMed  Google Scholar 

  75. van Oosterhout WPJ, Schoonman GG, van Zwet EW et al (2018) Female sex hormones in men with migraine. Neurology 91:e374–e381. https://doi.org/10.1212/WNL.0000000000005855

    Article  PubMed  CAS  Google Scholar 

  76. Schulte LH, May A (2016) The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139:1987–1993. https://doi.org/10.1093/brain/aww097

    Article  PubMed  Google Scholar 

  77. Schulte LH, Mehnert J, May A (2020) Longitudinal neuroimaging over 30 days: temporal characteristics of migraine. Ann Neurol 87:646–651. https://doi.org/10.1002/ana.25697

    Article  PubMed  Google Scholar 

  78. Maniyar FH, Sprenger T, Monteith T et al (2014) Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137:232–241. https://doi.org/10.1093/brain/awt320

    Article  PubMed  Google Scholar 

  79. Goadsby P, May A (1999) PET demonstration of hypothalamic activation in cluster headache. Neurology 52:1522–1522. https://doi.org/10.1212/WNL.52.7.1522

    Article  PubMed  CAS  Google Scholar 

  80. Schulte LH, Haji AA, May A (2020) Phase dependent hypothalamic activation following trigeminal input in cluster headache. J Headache Pain 21:30. https://doi.org/10.1186/s10194-020-01098-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Schulte LH, Allers A, May A (2017) Hypothalamus as a mediator of chronic migraine: Evidence from high-resolution fMRI. Neurology 88:2011–2016. https://doi.org/10.1212/WNL.0000000000003963

    Article  PubMed  Google Scholar 

  82. Arkink EB, Schmitz N, Schoonman GG et al (2017) The anterior hypothalamus in cluster headache. Cephalalgia 37:1039–1050. https://doi.org/10.1177/0333102416660550

    Article  PubMed  Google Scholar 

  83. May A, Burstein R (2019) Hypothalamic regulation of headache and migraine. Cephalalgia 39:1710–1719. https://doi.org/10.1177/0333102419867280

    Article  PubMed  PubMed Central  Google Scholar 

  84. Dodick D, Martin V (2004) Triptans and CNS Side-Effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 24:417–424. https://doi.org/10.1111/j.1468-2982.2004.00694.x

    Article  PubMed  CAS  Google Scholar 

  85. Skingle M, Birch PJ, Leighton GE, Humphrey PP (1990) Lack of antinociceptive activity of sumatriptan in rodents. Cephalalgia 10:207–212. https://doi.org/10.1046/j.1468-2982.1990.1005207.x

    Article  PubMed  CAS  Google Scholar 

  86. Visser WH, Terwindt GM, Reines SA et al (1996) Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group. Arch Neurol 53:1132–1137. https://doi.org/10.1001/archneur.1996.00550110072014

    Article  PubMed  CAS  Google Scholar 

  87. Sumatriptan Cluster Headache Study Group (1991) Treatment of acute cluster headache with sumatriptan. N Engl J Med 325:322–326. https://doi.org/10.1056/NEJM199108013250505

    Article  Google Scholar 

  88. Haane DY, Dirkx TH, Koehler PJ (2012) The history of oxygen inhalation as a treatment for cluster headache. Cephalalgia 32:932–939. https://doi.org/10.1177/0333102412452044

    Article  PubMed  Google Scholar 

  89. Cohen AS, Burns B, Goadsby PJ (2009) High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 302:2451. https://doi.org/10.1001/jama.2009.1855

    Article  PubMed  CAS  Google Scholar 

  90. Kudrow L (1981) Response of cluster headache attacks to oxygen inhalation. Headache 21:1–4. https://doi.org/10.1111/j.1526-4610.1981.hed2101001.x

    Article  PubMed  CAS  Google Scholar 

  91. Leone M, D’Amico D, Frediani F et al (2000) Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 54:1382–1385. https://doi.org/10.1212/WNL.54.6.1382

    Article  PubMed  CAS  Google Scholar 

  92. Ramadan N, Schultz L, Gilkey S (1997) Migraine prophylactic drugs: proof of efficacy, utilization and cost. Cephalalgia 17:73–80. https://doi.org/10.1046/j.1468-2982.1997.1702073.x

    Article  PubMed  CAS  Google Scholar 

  93. Tronvik E, Stovner LJ, Helde G et al (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 289:65–69. https://doi.org/10.1001/jama.289.1.65

    Article  PubMed  CAS  Google Scholar 

  94. Tronvik E, Wienecke T, Monstad I et al (2013) Randomised trial on episodic cluster headache with an angiotensin II receptor blocker. Cephalalgia 33:1026–1034. https://doi.org/10.1177/0333102413484989

    Article  PubMed  Google Scholar 

  95. Autonomic Technologies, Inc. (2018). Pathway M-1: Sphenopalatine Ganglion Stimulation for the AcuteTreatment of High Disability Migraine Headache. clinicaltrials.gov

    Google Scholar 

  96. Tassorelli C, Grazzi L, de Tommaso M et al (2018) Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Neurology 91:e364–e373. https://doi.org/10.1212/WNL.0000000000005857

    Article  PubMed  PubMed Central  Google Scholar 

  97. Goadsby PJ, de Coo IF, Silver N et al (2018) Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 38:959–969. https://doi.org/10.1177/0333102417744362

    Article  PubMed  Google Scholar 

  98. Tepper SJ (2018) History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment. Headache 58(Suppl 3):238–275. https://doi.org/10.1111/head.13379

    Article  PubMed  Google Scholar 

  99. Goadsby PJ, Dodick DW, Leone M et al (2019) Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med 381:132–141. https://doi.org/10.1056/NEJMoa1813440

    Article  PubMed  CAS  Google Scholar 

  100. Dodick DW, Goadsby PJ, Lucas C et al (2020) Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia 40:935–948. https://doi.org/10.1177/0333102420905321

    Article  PubMed  PubMed Central  Google Scholar 

  101. Dodick DW, Goadsby PJ, Ashina M et al (2022) Challenges and complexities in designing cluster headache prevention clinical trials: a narrative review. Headache 62:453–472. https://doi.org/10.1111/head.14292

    Article  PubMed  PubMed Central  Google Scholar 

  102. Cittadini E, May A, Straube A et al (2006) Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study. Arch Neurol 63:1537. https://doi.org/10.1001/archneur.63.11.nct60002

    Article  PubMed  Google Scholar 

  103. Drescher J, Khouri A, Amann TK et al (2021) Effectiveness of medication in cluster headache. BMC Neurol 21:174. https://doi.org/10.1186/s12883-021-02195-8

    Article  PubMed  PubMed Central  Google Scholar 

  104. Blau JN, Engel HO (2004) Individualizing treatment with verapamil for cluster headache patients. Headache 44:1013–1018. https://doi.org/10.1111/j.1526-4610.2004.04196.x

    Article  PubMed  Google Scholar 

  105. Barloese M, Haddock B, Lund NT et al (2018) Chronorisk in cluster headache: a tool for individualised therapy? Cephalalgia 38:2058–2067. https://doi.org/10.1177/0333102418769955

    Article  PubMed  Google Scholar 

  106. Snoer A, Vollesen ALH, Beske RP et al (2019) Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia 39:575–584. https://doi.org/10.1177/0333102419837154

    Article  PubMed  Google Scholar 

  107. Rossi HL, Recober A (2015) Photophobia in primary headaches. Headache 55:600–604. https://doi.org/10.1111/head.12532

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ashina H, Eigenbrodt AK, Seifert T et al (2021) Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment. Lancet Neurol 20:460–469. https://doi.org/10.1016/S1474-4422(21)00094-6

    Article  PubMed  Google Scholar 

  109. Lamonte M, Silberstein SD, Marcelis JF (1995) Headache associated with aseptic meningitis. Headache 35:520–526. https://doi.org/10.1111/j.1526-4610.1995.hed3509520.x

    Article  PubMed  CAS  Google Scholar 

  110. Al-Karagholi MA-M, Hansen JM, Guo S et al (2019) Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain 142:2644–2654. https://doi.org/10.1093/brain/awz199

    Article  PubMed  Google Scholar 

  111. Al-Karagholi MA-M, Ghanizada H, Waldorff Nielsen CA et al (2021) Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine. Pain 162:2512–2520. https://doi.org/10.1097/j.pain.0000000000002238

    Article  PubMed  CAS  Google Scholar 

  112. Botvinik-Nezer R, Holzmeister F, Camerer CF et al (2020) Variability in the analysis of a single neuroimaging dataset by many teams. Nature 582:84–88. https://doi.org/10.1038/s41586-020-2314-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Peng K-P, May A (2020) Targeting migraine treatment with neuroimaging-Pharmacological neuroimaging in headaches. Prog Brain Res 255:327–342. https://doi.org/10.1016/bs.pbr.2020.05.011

    Article  PubMed  Google Scholar 

  114. Bogucki A (1990) Studies on nitroglycerin and histamine provoked cluster headache attacks. Cephalalgia 10:71–75. https://doi.org/10.1046/j.1468-2982.1990.1002071.x

    Article  PubMed  CAS  Google Scholar 

  115. Lassen LH, Thomsen LL, Olesen J (1995) Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine. NeuroReport 6:1475–1479. https://doi.org/10.1097/00001756-199507310-00003

    Article  PubMed  CAS  Google Scholar 

  116. Thomsen LL, Kruuse C, Iversen HK, Olesen J (1994) A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1:73–80. https://doi.org/10.1111/j.1468-1331.1994.tb00053.x

    Article  PubMed  CAS  Google Scholar 

  117. Lassen L, Haderslev P, Jacobsen V et al (2002) Cgrp may play a causative role in migraine. Cephalalgia 22:54–61. https://doi.org/10.1046/j.1468-2982.2002.00310.x

    Article  PubMed  CAS  Google Scholar 

  118. Schytz HW, Birk S, Wienecke T et al (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132:16–25. https://doi.org/10.1093/brain/awn307

    Article  PubMed  Google Scholar 

  119. Rahmann A, Wienecke T, Hansen J et al (2008) Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28:226–236. https://doi.org/10.1111/j.1468-2982.2007.01497.x

    Article  PubMed  CAS  Google Scholar 

  120. Pellesi L, Al-Karagholi MA-M, Chaudhry BA et al (2020) Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers. Cephalalgia 40:1212–1223. https://doi.org/10.1177/0333102420937655

    Article  PubMed  Google Scholar 

Download references

Availability data and materials

Not applicable.

Funding

The Research Fund of Rigshospitalet (E-23327-04). The Lundbeck Foundation for supporting the study through the Professor Grant (R310–2018-3711).

Author information

Authors and Affiliations

Authors

Contributions

MMK, KPP and MA initiated the review drafting and revision of the article. ASP, IDB and GMT contributed with a critical review of the article. MMK and KPP prepared figures and tables. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Messoud Ashina.

Ethics declarations

Competing interests

MMK, KPP, ASP and IDB report no conflict of interest. GMT has received consulting fees and honoraria for lectures/presentations from Allergan, Eli Lily, Lundbeck, Novartis and Teva. Personal fees from AbbVie/Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva. MA participated in clinical trials as the principal investigator for AbbVie/Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Teva. MA received a research grant (institutional) from Lundbeck Foundation, Novo Nordisk Foundation, Novartis. MA has no ownership interest and does not own stocks of any pharmaceutical company. MA serves as associate editor of Cephalalgia, associate editor of the Journal of Headache and Pain, and associate editor of Brain.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Karagholi, M.AM., Peng, KP., Petersen, A.S. et al. Debate: Are cluster headache and migraine distinct headache disorders?. J Headache Pain 23, 151 (2022). https://doi.org/10.1186/s10194-022-01504-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s10194-022-01504-x

Keywords