ArticlePDF AvailableLiterature Review

Debate: Are cluster headache and migraine distinct headache disorders?

Authors:
  • Danish Institute for Health Services Research

Abstract and Figures

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 .
Trigeminovascular system (TVS). Generation of Cluster headache (CH) involves the trigeminocervical complex (TCC), the parasympathetic nerve fibers (trigeminal autonomic reflex (TAR)), and the hypothalamus [21–29]. 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
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.
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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 [3335]. 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%
[4951]. 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 [2129]. 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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Page 6 of 13
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 (OR1.30) than
for migraine (OR1.09) 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 [6668].
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% [3840] 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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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
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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Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
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 [8890]. 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
References
1. Headache Classification Committee of the International Headache Soci‑
ety (IHS) (2018) The International Classification of Headache Disorders,
3rd edition. Cephalalgia 38:1–211. https:// doi. org/ 10. 1177/ 03331 02417
738202
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
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
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. 18031 38.x
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. 00000 00000
003715
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/ 03331 02419 828967
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
8. Eigenbrodt AK, Ashina H, Khan S et al (2021) Diagnosis and manage‑
ment of migraine in ten steps. Nat Rev Neurol 17:501–514. https:// doi.
org/ 10. 1038/ s41582‑ 021‑ 00509‑5
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
10. Nelson RF (1970) Cluster migraine‑‑an unrecognized common entity.
Can Med Assoc J 103:1026–1030
11. Sjöstrand C, Russell M, Ekbom K et al (2005) Familial cluster headache.
is atypical cluster headache in family members part of the clinical spec‑
trum? Cephalalgia 25:1068–1077. https:// doi. org/ 10. 1111/j. 1468‑ 2982.
2005. 00964.x
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/ 03331 02421 10304 99
13. Barloese MCJ (2015) Neurobiology and sleep disorders in clus‑
ter headache. J Headache Pain 16:562. https:// doi. org/ 10. 1186/
s10194‑ 015‑ 0562‑0
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
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
16. Ekbom K, Svensson DA, Träff H, Waldenlind E (2002) Age at onset and
sex ratio in cluster headache: observations over three decades. Cepha‑
lalgia 22:94–100. https:// doi. org/ 10. 1046/j. 1468‑ 2982. 2002. 00318.x
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
18. Rasmussen BK, Olesen J (1992) Migraine with aura and migraine with‑
out aura: an epidemiological study. Cephalalgia 12:221–228; discussion
186. https:// doi. org/ 10. 1046/j. 1468‑ 2982. 1992. 12042 21.x
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
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
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
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/ 03331 02412 473667
23. Akerman S, Holland PR, Summ O et al (2012) A translational in vivo
model of trigeminal autonomic cephalalgias: therapeutic characteriza‑
tion. Brain 135:3664–3675. https:// doi. org/ 10. 1093/ brain/ aws249
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 11 of 13
Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
24. Robert C, Bourgeais L, Arreto C‑D et al (2013) Paraventricular Hypo‑
thalamic Regulation of Trigeminovascular Mechanisms Involved in
Headaches. J Neurosci 33:8827–8840. https:// doi. org/ 10. 1523/ JNEUR
OSCI. 0439‑ 13. 2013
25. May A, Goadsby P (2016) The enigma of the interconnection of trigemi‑
nal pain and cranial autonomic symptoms. Cephalalgia 36:727–729.
https:// doi. org/ 10. 1177/ 03331 02415 611410
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/ 00004 647‑ 19990 2000‑ 00001
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
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
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/ 03331 02416 649092
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/ 03331 02413 476370
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/
03331 02420 921156
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/ 03331 02417
738250
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
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. 37010 21.x
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/ 03331 02417 731773
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/ 03331 02417 726498
37. Giffin NJ, Ruggiero L, Lipton RB et al (2003) Premonitory symptoms in
migraine: an electronic diary study. Neurology 60:935–940
38. Louter MA, Bosker JE, van Oosterhout WPJ et al (2013) Cutaneous allo‑
dynia as a predictor of migraine chronification. Brain 136:3489–3496.
https:// doi. org/ 10. 1093/ brain/ awt251
39. Bigal ME, Ashina S, Burstein R et al (2008) Prevalence and characteris‑
tics of allodynia in headache sufferers: a population study. Neurology
70:1525–1533. https:// doi. org/ 10. 1212/ 01. wnl. 00003 10645. 31020. b1
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
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. 00000
00000 000891
42. Choi J‑Y, Oh K, Kim B‑J et al (2009) Usefulness of a photophobia ques‑
tionnaire in patients with migraine. Cephalalgia 29:953–959. https:// doi.
org/ 10. 1111/j. 1468‑ 2982. 2008. 01822.x
43. Vingen JV, Pareja J, Stovner L (1998) Quantitative evaluation of photo‑
phobia and phonophobia in cluster headache. Cephalalgia 18:250–256.
https:// doi. org/ 10. 1046/j. 1468‑ 2982. 1998. 18052 50.x
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.
18052 43.x
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
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/ 03331 02410 391486
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
48. Chu MK, Kim B‑S, Chung P‑W et al (2021) Clinical features of cluster
headache without cranial autonomic symptoms: results from a pro‑
spective multicentre study. Sci Rep 11:6916. https:// doi. org/ 10. 1038/
s41598‑ 021‑ 86408‑7
49. Barbanti P, Fabbrini G, Pesare M et al (2002) Unilateral Cranial Auto‑
nomic Symptoms in Migraine. Cephalalgia 22:256–259. https:// doi. org/
10. 1046/j. 1468‑ 2982. 2002. 00358.x
50. Obermann M, Yoon M‑S, Dommes P et al (2007) Prevalence of trigemi‑
nal autonomic symptoms in migraine: a population‑based study.
Cephalalgia 27:504–509. https:// doi. org/ 10. 1111/j. 1468‑ 2982. 2007.
01316.x
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
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
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.
00000 00000 001343
54. Brandt RB, Cnossen VM, Doesborg PG et al (2022) Unilateral increased
visual sensitivity in cluster headache: a cross‑sectional study. Cephalal‑
gia 42:722–729. https:// doi. org/ 10. 1177/ 03331 02422 10776 64
55. Burstein R, Yarnitsky D, Goor‑Aryeh I et al (2000) An association
between migraine and cutaneous allodynia. Ann Neurol 47:614–624
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
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. 18020 91.x
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
59. Russell M (1997) Genetic epidemiology of migraine and cluster head‑
ache. Cephalalgia 17:683–701. https:// doi. org/ 10. 1046/j. 1468‑ 2982.
1997. 17066 83.x
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
61. Russell MB, Andersson PG, Thomsen LL, Iselius L (1995) Cluster head‑
ache 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
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
63. Harder AVE, Winsvold BS, Noordam R et al (2021) Genetic susceptibil
ity loci in genomewide association study of cluster headache. Ann
Neurol 90:203–216. https:// doi. org/ 10. 1002/ ana. 26146
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
65. Ashina M (2020) Migraine. N Engl J Med 383:1866–1876. https:// doi.
org/ 10. 1056/ NEJMr a1915 327
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 12 of 13
Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
67. Hoffmann J, May A (2018) Diagnosis, pathophysiology, and manage
ment of cluster headache. Lancet Neurol 17:75–83. https:// doi. org/
10. 1016/ S1474‑ 4422(17) 30405‑2
68. May A (2005) Cluster headache: pathogenesis, diagnosis, and
management. Lancet 366:843–855. https:// doi. org/ 10. 1016/ S0140‑
6736(05) 67217‑0
69. Vollesen ALH, Snoer A, Beske RP et al (2018) Effect of infusion of
calcitonin gene‑related peptide on cluster headache attacks: a ran
domized clinical trial. JAMA Neurol 75:1187. https:// doi. org/ 10. 1001/
jaman eurol. 2018. 1675
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/ 03331 02421 989617
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/ 03331 02420 940689
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/ 03331 02420 981666
73. Ashina H, Iljazi A, Al‑Khazali HM et al (2020) Hypersensitivity to calci
tonin gene‑related peptide in post‑traumatic headache. Ann Neurol
88:1220–1228. https:// doi. org/ 10. 1002/ ana. 25915
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
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. 00000 00000 005855
76. Schulte LH, May A (2016) The migraine generator revisited: continu
ous scanning of the migraine cycle over 30 days and three sponta
neous attacks. Brain 139:1987–1993. https:// doi. org/ 10. 1093/ brain/
aww097
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
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
79. Goadsby P, May A (1999) PET demonstration of hypothalamic activa
tion in cluster headache. Neurology 52:1522–1522. https:// doi. org/
10. 1212/ WNL. 52.7. 1522
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
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. 00000 00000 003963
82. Arkink EB, Schmitz N, Schoonman GG et al (2017) The anterior hypo
thalamus in cluster headache. Cephalalgia 37:1039–1050. https:// doi.
org/ 10. 1177/ 03331 02416 660550
83. May A, Burstein R (2019) Hypothalamic regulation of headache and
migraine. Cephalalgia 39:1710–1719. https:// doi. org/ 10. 1177/ 03331
02419 867280
84. Dodick D, Martin V (2004) Triptans and CNS Side‑Effects: pharmacoki
netic and metabolic mechanisms. Cephalalgia 24:417–424. https://
doi. org/ 10. 1111/j. 1468‑ 2982. 2004. 00694.x
85. Skingle M, Birch PJ, Leighton GE, Humphrey PP (1990) Lack of antino‑
ciceptive activity of sumatriptan in rodents. Cephalalgia 10:207–212.
https:// doi. org/ 10. 1046/j. 1468‑ 2982. 1990. 10052 07.x
86. Visser WH, Terwindt GM, Reines SA et al (1996) Rizatriptan vs
sumatriptan in the acute treatment of migraine. A placebo‑con
trolled, dose‑ranging study. Dutch/US Rizatriptan Study Group. Arch
Neurol 53:1132–1137. https:// doi. org/ 10. 1001/ archn eur. 1996. 00550
11007 2014
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/ NEJM1 99108 01325 0505
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/ 03331 02412 452044
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
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.
hed21 01001.x
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
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. 17020 73.x
93. Tronvik E, Stovner LJ, Helde G et al (2003) Prophylactic treatment of
migraine with an angiotensin II receptor blocker: a randomized con‑
trolled trial. JAMA 289:65–69. https:// doi. org/ 10. 1001/ jama. 289.1. 65
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/ 03331 02413 484989
95. Autonomic Technologies, Inc. (2018). Pathway M‑1: Sphenopalatine
Ganglion Stimulation for the AcuteTreatment of High Disability
Migraine Headache. clini caltr ials. gov
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.
00000 00000 005857
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/ 03331 02417 744362
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
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/ NEJMo a1813 440
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/ 03331 02420 905321
101. Dodick DW, Goadsby PJ, Ashina M et al (2022) Challenges and com‑
plexities in designing cluster headache prevention clinical trials: a narra‑
tive review. Headache 62:453–472. https:// doi. org/ 10. 1111/ head. 14292
102. Cittadini E, May A, Straube A et al (2006) Effectiveness of intranasal zol‑
mitriptan in acute cluster headache: a randomized, placebo‑controlled,
double‑blind crossover study. Arch Neurol 63:1537. https:// doi. org/ 10.
1001/ archn eur. 63. 11. nct60 002
103. Drescher J, Khouri A, Amann TK et al (2021) Effectiveness of medica‑
tion in cluster headache. BMC Neurol 21:174. https:// doi. org/ 10. 1186/
s12883‑ 021‑ 02195‑8
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
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/ 03331 02418 769955
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/ 03331 02419 837154
107. Rossi HL, Recober A (2015) Photophobia in primary headaches. Head‑
ache 55:600–604. https:// doi. org/ 10. 1111/ head. 12532
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
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. hed35 09520.x
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 13 of 13
Al‑Karagholietal. The Journal of Headache and Pain (2022) 23:151
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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. 00000 00000 002238
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
113. Peng K‑P, May A (2020) Targeting migraine treatment with neuroim‑
aging‑Pharmacological neuroimaging in headaches. Prog Brain Res
255:327–342. https:// doi. org/ 10. 1016/ bs. pbr. 2020. 05. 011
114. Bogucki A (1990) Studies on nitroglycerin and histamine provoked clus‑
ter headache attacks. Cephalalgia 10:71–75. https:// doi. org/ 10. 1046/j.
1468‑ 2982. 1990. 10020 71.x
115. Lassen LH, Thomsen LL, Olesen J (1995) Histamine induces migraine via
the H1‑receptor. Support for the NO hypothesis of migraine. NeuroRe‑
port 6:1475–1479. https:// doi. org/ 10. 1097/ 00001 756‑ 19950 7310‑ 00003
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. tb000 53.x
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
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
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
120. Pellesi L, Al‑Karagholi MA‑M, Chaudhry BA et al (2020) Two‑hour infu‑
sion of vasoactive intestinal polypeptide induces delayed headache
and extracranial vasodilation in healthy volunteers. Cephalalgia
40:1212–1223. https:// doi. org/ 10. 1177/ 03331 02420 937655
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Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of "cluster headache," and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.
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Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
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Background: Whilst cranial autonomic symptoms (CAS) are typically associated with trigeminal autonomic cephalalgias (TAC's), they have also been reported in migraine. Identification and understanding of these symptoms in migraine is important to ensure timely diagnosis and effective management. Methods: Migraineurs seen in a tertiary headache service between 2014 and 2018 (n = 340): cohort one, and a separate cohort of headache patients seen between 2014-May 2021 reporting voice change, or throat swelling, or both, as CAS were selected (n = 64): cohort two. We performed a service evaluation of our records regarding age, sex, diagnosis, headache and CAS frequency and laterality as acquired from the first consultation, during which a detailed headache history is taken by a headache trained physician. Results: Cohort 1: Mean age 43 (range 14-94, SD 15). The most common diagnosis was chronic migraine (78%). Median monthly headache frequency was 26 days (IQR 15-75). At least one CAS was reported in 74%, with a median of two (IQR 0-3). The most common were nasal congestion (32%), lacrimation (31%) and aural fullness (25%). Most patients reported their most common headache as unilateral (80%) and with it strictly unilateral CAS (64%). There was a positive association between headache and CAS laterality (χ21 = 20.7, P < 0.001), with a positive correlation between baseline headache frequency and number of CAS reported (r = 0.11, P = 0.047). Cohort two: mean age 49 (range 23-83, SD 14). Diagnoses were chronic migraine (50%), chronic cluster headache (11%), undifferentiated continuous lateralised headache (9%), SUNCT/SUNA (8%), hemicrania continua (8%), episodic migraine (8%), episodic cluster headache (3%) and trigeminal neuropathies (3%). Most (89%) described trigeminal distribution pain; 25% involving all three divisions. Throat swelling was reported by 54, voice change by 17, and both by 7. The most common CAS reported were lacrimation (n = 47), facial swelling (n = 45) and rhinorrhoea (n = 37). There was significant agreement between the co-reporting of throat swelling (χ21 = 7.59, P = 0.013) and voice change (χ21 = 6.49, P = 0.02) with aural fullness. Conclusions: CAS are common in migraine, are associated with increasing headache frequency and tend to lateralise with headache. Voice change and throat swelling should be recognized as possible parasympathetically-mediated CAS. They may be co-associated and associated with aural fullness, suggesting a broadly somatotopic endophenotype.
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Objective The presence of aura is rare in cluster headache, and even rarer in other trigeminal autonomic cephalalgias. We hypothesized that the presence of aura in patients with trigeminal autonomic cephalalgias is frequently an epiphenomenon and mediated by comorbid migraine with aura. Methods The study retrospectively reviewed 480 patients with trigeminal autonomic cephalalgia in a tertiary medical center for 10 years. Phenotypes and temporal correlation of aura with headache were analyzed. Trigeminal autonomic cephalalgia patients with aura were further followed up in a structured telephone interview. Results Seventeen patients with aura (3.5%) were identified from 480 patients with trigeminal autonomic cephalalgia, including nine with cluster headache, one with paroxysmal hemicrania, three with hemicrania continua, and four with probable trigeminal autonomic cephalalgia. Compared to trigeminal autonomic cephalalgia patients without aura, trigeminal autonomic cephalalgia patients with aura were more likely to have a concomitant diagnosis of migraine with aura (odds ratio [OR] = 109.0, 95% CI 30.9–383.0, p < 0.001); whereas the risk of migraine without aura remains similar between both groups (OR = 1.10, 95% CI = 0.14–8.59, p = 0.931). Aura was more frequently accompanied with migraine-like attacks, but not trigeminal autonomic cephalalgia attacks. Interpretation In most patients with trigeminal autonomic cephalalgia, the presence of aura is mediated by the comorbidity of migraine with aura. Aura directly related to trigeminal autonomic cephalalgia attack may exist but remains rare. Our results suggest that aura may not be involved in the pathophysiology of trigeminal autonomic cephalalgia.
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Background The paroxysmal nature of migraine is a hallmark of the disease. Some patients report increased attack frequency at certain seasons or towards the end of the week, while others experience diurnal variations of migraine attack onset. This systematic review investigates the chronobiology of migraine and its relation to the periodicity of attacks in existing literature to further understand the oscillating nature of migraine. Main body PubMed and Embase were systematically searched and screened for eligible articles with outcome measures relating to a circadian, weekly or seasonal distribution of migraine attacks. We found that the majority of studies reported morning hours (6 am–12 pm) as the peak time of onset for migraine attacks. More studies reported Saturday as weekly peak day of attack. There was no clear seasonal variation of migraine due to methodological differences (primarily related to location), however four out of five studies conducted in Norway reported the same yearly peak time indicating a possible seasonal periodicity phenomenon of migraine. Conclusions The findings of the current review suggest a possible role of chronobiologic rhythms to the periodicity of migraine attacks. Future studies are, however, still needed to provide more knowledge of the oscillating nature of migraine.
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Objective To identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model, for each cohort. The two cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified two replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10⁻¹⁷, OR [95%CI] = 1.51 [1.37–1.66]) and rs4519530 (p = 6.98 x 10⁻¹⁷, OR = 1.47 [1.34–1.61]) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10⁻⁸, OR = 1.36 [1.22–1.52]) and rs11153082 (p = 1.85 x 10⁻⁸, OR = 1.30 [1.19–1.42]) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome-wide-significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to e.g. treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. This article is protected by copyright. All rights reserved.
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Objective Identifying common genetic variants that confer genetic risk for cluster headache. Methods We conducted a case–control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and controls from the Netherlands Epidemiology of Obesity Study (NEO) (n = 1,457), representing the general population. Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results An association was found with cluster headache for four independent loci (r² < 0.1) with genome-wide significance (p < 5 x 10⁻⁸), rs11579212 (odds ratio (OR) = 1.51, 95% CI 1.33–1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of the phenotype. SNPs rs11579212, rs10184573 and rs976357, as proxy SNP for rs2499799 (r² = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache. Interpretation This GWAS identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. This article is protected by copyright. All rights reserved.
Article
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Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up. In this Consensus Statement, which is endorsed by the European Headache Federation and the European Academy of Neurology, an expert panel provides recommendations for the diagnosis and management of migraine to support clinical decision-making by general practitioners, neurologists and headache specialists.
Article
Background and objectives: Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache. Methods: We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine. Results: Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 ± 8.0 vs. 5.2 ± 5.5, chronic cluster headache: 13.7 ± 8.4 vs 5.6 ± 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 ± 5.2 vs 3.6 ± 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 ± 0.5 vs 3.8 ± 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 ± 5.5 vs. 3.7 ± 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants. Conclusion: Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.