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 .

Full text

Al‑Karagholietal.
The Journal of Headache and Pain (2022) 23:151
https://doi.org/10.1186/s10194‑022‑01504‑x
REVIEW
Debate: Are cluster headache andmigraine
distinct headache disorders?
Mohammad Al‑Mahdi Al‑Karagholi1†, Kuan‑Po Peng2†, Anja Sofie Petersen1, Irene De Boer3,
Gisela M. Terwindt3 and Messoud Ashina1*
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, dis‑
cuss whether cluster headache and migraine should indeed be considered as two distinct primary headaches, and
propose recommendations for future studies.
Keywords: CGRP, Nitric oxide, PACAP, Trigeminovascular system, Cranial autonomic symptoms
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Open Access
The Journal of Headache
and Pain
†Mohammad Al‑Mahdi Al‑Karagholi and Kuan‑Po Peng contributed equally
to this work.
*Correspondence: ashina@dadlnet.dk
1 Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup,
Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar
Hansen Vej 5, DK‑2600 Glostrup, Denmark
Full list of author information is available at the end of the article
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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
Introduction
In the International Classification of Headache Disor-
ders (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, respec-
tively [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). e prevalence of
migraine in individuals diagnosed with CH does not
differ from the general population [5]. Important clini-
cal differences between cluster headache and migraine
headache include duration and frequency of attacks. A
CH attack lasts between 15 and 180 minutes, and mul-
tiple attacks per day may occur, whereas the duration of
a migraine attack is between 4 and 72 hours, and recur-
rence is defined as a headache within 22 hours of initial
successful treatment of a migraine attack (2-hour head-
ache 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 cra-
nial 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]. ese 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 chronobio-
logical features, mainly circadian (most frequently noctur-
nal) 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]. e 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].
Migraine attacks are characterized by recurrent unilat-
eral 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
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. youtu be. com/ watch?v= uUimm nDVTTE.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
Table 1 ICHD‑3 Diagnostic criteria for cluster headache
Cluster headache
A. At least five attacks fulfilling criteria B–D
B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes (when untreated)
C. Either or both of the following:
1. At least one of the following symptoms or signs, ipsilateral to the headache:
a) Conjunctival injection and/or lacrimation
b) Nasal congestion and/or rhinorrhoea
c) Eyelid oedema
d) Forehead and facial sweating
e) Miosis and/or ptosis
2. A sense of restlessness or agitation
D. Occurring with a frequency between one every other day and eight per day
E. Not better accounted for by another ICHD‑3 diagnosis.
Episodic cluster headache
A. Attacks fulfilling criteria for cluster headache and occurring in bouts (cluster periods)
B. At least two cluster periods lasting from seven days to one year (when untreated) and separated by pain‑free remission periods of ≥3 months.
Chronic cluster headache
A. Attacks fulfilling criteria for cluster headache and occurring in bouts (cluster periods)
B. Occurring without a remission period, or with remissions lasting <3 months for at least one year.
Table 2 ICHD‑3 Diagnostic Criteria for Migraine
Migraine without aura
A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated)
C. Headache has at least two of the following four characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
D. During headache at least one of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
E. Not better accounted for by another ICHD‑3 diagnosis.
Migraine with aura
A. At least two attacks fulfilling criteria B and C
B. One or more of the following fully reversible aura symptoms:
1. Visual
2. Sensory
3. Speech and/or language
4. Motor
5. Brainstem
6. Retinal
C. At least three of the following six characteristics:
1. At least one aura symptom spreads gradually over ≥5 minutes
2. Two or more aura symptoms occur in succession
3. Each individual aura symptom lasts 5–60 minutes
4. At least one aura symptom is unilateral
5. At least one aura symptom is positive
6. The aura is accompanied, or followed within 60 minutes, by headache
D. Not better accounted for by another ICHD‑3 diagnosis.
Chronic migraine
A. Headache (migraine‑like or tension‑type‑like) on ≥15 days/month for >3 months, and fulfilling criteria B and C
B. Occurring in a patient who has had at least five attacks fulfilling criteria B–D for migraine with‑ out aura and/or criteria B and C for migraine with
aura
C. On ≥8 days/month for >3 months, fulfilling any of the following:
1. Criteria C and D for migraine without aura
2. Criteria B and C for migraine with aura
3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
D. Not better accounted for by another ICHD‑3 diagnosis.
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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
with migraine reported bilateral headache [18]. Migraine
is a life span disease with an age-dependent change. e
prevalence of migraine increases with age and peaks
at 35–39 years of age, followed by a decline [19]. ese
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 [33–35]. Notably, the proportion is
similar to the prevalence of migraine in the general popu-
lation [3]. Comorbid CH in migraine cohorts has yet to
be investigated. is partially reflects the relatively low
prevalence of CH in the general population [2]. Whether
Fig. 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 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
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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
the comorbidity suggests a shared disease mechanism or
a co-occurrence by chance requires further investigation,
especially in longitudinal studies.
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%
[49–51]. e 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 typi-
cal 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 sensitiv-
ity 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
Fig. 3 Trigeminovascular system (T VS). Generation of Cluster headache (CH) involves the trigeminocervical complex (TCC), the parasympathetic
nerve fibers (trigeminal autonomic reflex (TAR)), and the hypothalamus [21–29]. 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
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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
accompanying migraine attacks [55] and is considered
a clinical marker of central sensitization [38], and a risk
factor for migraine chronification [38] but not associ-
ated with chronic CH [41]. Interestingly, 36% of patients
with CH report allodynia during attacks [41]. Female
gender, young age at onset, lifetime depression, comor-
bid migraine, and recent attacks were independent risk
factors for allodynia. e 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 dur-
ing attacks [46, 47]. While light physical activity exacer-
bates migraine headache, and migraine patients usually
lie down during attacks (Table3) [1].
Migraine patients may experience prodromal symp-
toms such as yawning, changes in mood and diffi-
culty 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 head-
ache, while the aura in CH patient is often caused by a
comorbid migraine with aura (Fig.2) [12]. us, the clini-
cal manifestations of both primary headaches overlap to
some extent; however, the striking circannual and circa-
dian periodicity, duration of attacks and some associated
symptoms are clearly different (Fig.2).
Disease Mechanisms
Genetics
e 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 over-
lap between them remained a conundrum.
e 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 inde-
pendently 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 previ-
ous known migraine locus. Moreover, the association had
the same effect direction for both CH and migraine. Not-
edly, the effect sizes were higher for CH (OR≈1.30) than
for migraine (OR≈1.09) for this locus [63, 64]. e 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. e effect size might
also be influenced by the CH populations, that were
very homogenous and had validated diagnosis accord-
ing 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. is may suggest both partly shared
and partly distinct involved biological mechanisms.
Pathophysiology
e 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 calci-
tonin gene-related peptide (CGRP), pituitary adenylate
cyclase-activating polypeptide-38 (PACAP38) and vaso-
active intestinal polypeptide (VIP). To explore signaling
pathways within the TVS, several pharmacological com-
pounds were used to induce CH attacks and migraine
attacks including histamine, glyceryl trinitrate (GTN),
CGRP, PACAP38 and VIP [66–68].
Pharmacological triggers for migraine attacks are effec-
tive triggers for CH attacks (Table 4). In randomized
Table 3 Clinical presentation. Comparison of clinical presentation
between cluster headache and migraine
Migraine Cluster headache
Unilateral pain 60% 100%
Intensity Moderate to severe Severe – very severe
Duration 4–72 hours 15–180 minutes
Circadian rhythm Less prominent Prominent
Presence of prodromes 83.3% [36] 72% [37]
Ictal allodynia 40–70% [38–40] 36% [41]
Photophobia (ictal) 80% [42] 91% [43]
Phonophobia (ictal) 98% [44] 89% [43]
Cranial autonomic symp‑
tom
Restlessness
74% [45]
Physical activity
usually worsens
headache
Nearly 100%
70% [46]‑88% [47]
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Table 4 Provocation studies. Cluster headache and migraine have several pharmacological triggers in common but different
methodological approach have been applied in attack induction
Blue indicates induction rate, green indicates median time to onset, and red indicates study design. RCT Randomized clinical trial, ECHA Episodic cluster headache in
active phase, ECHR Episodic cluster headache in remission phase, CCH Chronic cluster headache, and NI Not Investigated
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placebo-controlled clinical trials (RCT), GTN and
CGRP induced CH attacks [69, 70]. One RCT investi-
gated 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. Inter-
estingly, 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]. ese observations suggest that
CH and migraine share anatomical structures and patho-
physiological mechanisms but differ in signaling cascades
leading to attack initiation. Notably, participants diag-
nosed 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.
Gender-related etiology of CH and migraine sug-
gests 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 hor-
mone 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 hypo-
thalamic activation up to 48 hours before migraine head-
ache [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. e hypothalamus is acti-
vated during the ictal period of CH attacks [79]. A recent
fMRI study revealed an activation of the posterior hypo-
thalamus 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 chrono-
logical rhythm [83] and its specific subnuclei may explain
prodromal symptoms [83], it would be plausible to sug-
gest 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 nox-
ious 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]. e
exact underlying mechanism for this effect is uncertain,
and several explanations have been proposed, including
inhibition of the trigeminoautonomic reflex (TAR), mod-
ulation of neurotransmitters, and cerebral vasoconstric-
tion [88–90]. To date, no RCT has assessed the efficacy of
oxygen therapy in migraine patients.
e 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 parasympa-
thetic outflow by sphenopalatine ganglion (SPG) stimu-
lation 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 stimu-
lation (nVNS) showed significant efficacy in aborting
Table 5 Treatment. Comparison of treatment responses between
cluster headache and migraine
+++ ecacy proved in ≥2 randomized placebo‑controlled studies
++ ecacy proved in 1 randomized placebo‑controlled study
+ open label studies
‑ negative randomized placebo‑controlled study
nVNS Non‑invasive vagus nerve stimulation, SPG Sphenopalatine ganglion
a SPG block
b SPG stimulation
Migraine Episodic cluster headache
Triptan +++ +++
CGRP‑mAb +++ ++/−
Oxygen ++ +++
Steroid ++ ++
Topiramate +++ +
Melatonin +++ ++
nVNS ++ ++
SPG modulation ++/− (chronic
migraine)a++ (chronic cluster headache)b
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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
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 effi-
cacy 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, gal-
canezumab did not meet its primary and key second-
ary endpoints [100]. Clinical trials with fremanezumab
(NCT02945046 with episodic and chronic CH partici-
pants; and NCT02964338 with chronic CH participants)
were discontinued due to the negative results of the mid-
term futility analysis. ese 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]. Interest-
ingly, 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 sus-
ceptible to recurrent attacks. Another possible explana-
tion 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 lev-
els 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 com-
ponent. e latest CH GWASs indicated that they
share at least one genetic locus. Increasing sample size
(mainly for the CH cohorts currently available for analy-
ses) and meta-analyses of the genetic data available will
further elucidate shared and distinct genetic compo-
nents of the disorders. Despite the abundance of shared
clinical features between CH and migraine, none of the
headache features are specific to any headache diagno-
sis. For example, photophobia is not restricted to CH
or migraine [107]. Patients with secondary headaches
including post-traumatic headache and headache attrib-
uted to intracranial infection (e.g. meningitis) may report
photophobia and other clinical manifestation that mimic
primary headaches [108, 109]. us, none of the clini-
cal features are diagnosis-specific and possibly simply
reflects the activation of the trigeminal pain pathway.
e presence or absence of certain associated symptoms
may reflect the degree of activation: e.g., CAS might only
accompany severe headaches. e most striking charac-
teristic of CH is the short attack duration. Regardless of
the severity and intensity of the attack, the attack stops
spontaneously within 180 minutes. e mechanism of
how cluster and migraine attacks stop spontaneously
remains unknown. In discussing the structures and mol-
ecules involved in CH and migraine, numerous questions
remained to be answered: 1) molecular pathways respon-
sible for genesis of attacks; 2) factors modulating suscep-
tibility to attacks; 3) the precise mechanisms and order of
events behind the initiation of attacks; 4) molecular path-
ways 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 potas-
sium channels (BKCa) channels [111] served as highly
effective migraine attack triggers (95–100%). Clinical tri-
als 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 ana-
lytical 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 com-
parison between CH and migraine will be necessary, and
these studies are still lacking. Furthermore, functional
imaging studies investigating patients with CH are diffi-
cult to conduct because patients usually have restlessness
during their attacks.
Although patients with CH and migraine share sev-
eral specific treatment options, the mechanism or the
site of action remains largely uncertain. Another criti-
cal 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 diag-
nostic criterion in paroxysmal hemicrania and hemi-
crania continua. In addition, for any given medication,
there are always clinical responders vs. clinical non-
responders. e diverse response to a specific medi-
cation 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).
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 10 of 13
Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
Conclusions
CH and migraine share some clinical features, including
non-headache (pre) ictal features such as prodromal fea-
tures, (inter) ictal visual hypersensitivity, ictal allodynia
and cranial autonomic features. Demographics, genetics
and chronological patterns suggest partly overlap, but
also important differences in pathophysiological mecha-
nisms. 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 dif-
fer. 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.
Availability data and materials
Not applicable.
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 ar ticle. MMK and
KPP prepared figures and tables. The author(s) read and approved the final
manuscript.
Funding
The Research Fund of Rigshospitalet (E‑23327‑04). The Lundbeck Foundation
for supporting the study through the Professor Grant (R310–2018‑3711).
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 Founda‑
tion, 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.
Author details
1 Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup,
Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar
Hansen Vej 5, DK‑2600 Glostrup, Denmark. 2 Department of Systems Neurosci‑
ence, University Medical Center Hamburg‑Eppendorf, Hamburg, Germany.
3 Department of Neurology, Leiden University Medical Center, Leiden,
Netherlands.
Received: 6 September 2022 Accepted: 29 September 2022
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