Clin Auton Res
DOI 10.1007/s10286-017-0468-9
REVIEW
The pathophysiology of the trigeminal autonomic cephalalgias,
with clinical implications
Mads C. J. Barloese1,2   
Received: 5 August 2017 / Accepted: 11 September 2017
© Springer-Verlag GmbH Germany 2017
Abstract  The hallmark of primary headaches belonging to
the group known as the trigeminal autonomic cephalalgias
is unilateral headache accompanied by cranial autonomic
symptoms. Being relatively rare and poorly understood, they
represent a clinical challenge, leading to underdiagnosis and
undertreatment. While the headache is the most obvious
and disabling symptom, it is only part of a complex symp-
tomatology which hints at the involved pathophysiological
mechanisms. Activation of the trigeminal-autonomic reflex
results in the aforementioned cranial autonomic symptoms,
which are well understood; however, it is obvious that this
brainstem reflex is regulated by higher centers that seem-
ingly play a pivotal role in the attacks and the wide range of
other symptoms indicating a homeostatic disturbance. These
symptoms, as well as a number of well-validated findings,
implicate the hypothalamus in the pathophysiology. over the
course of the past 2–3 decades, novel therapies and tech-
nological advances have helped increase our knowledge of
these clinical syndromes, and will likely continue to do so in
the coming years as we witness the arrival of new drugs and
neurostimulation options. In this review, the clinical presen-
tation for cluster headache, paroxysmal hemicrania, short-
lasting unilateral neuralgiform headache with conjunctival
injection and tearing, and hemicrania continua is covered,
along with our current understanding of the common patho-
physiology and clinical manifestations.
* Mads C. J. Barloese
mads.christian.johannes.barloese@barloese.net
1
Department of Clinical Physiology, Nuclear Medicine
and PET, Rigshospitalet‑Glostrup, University
of Copenhagen, Copenhagen, Denmark
2 of the TACs and then focus on the current understanding of
Danish Headache Center, Department of Neurology,
Rigshospitalet‑Glostrup, University of Copenhagen,
Copenhagen, Denmark
Keywords  Trigeminal autonomic cephalalgias ·
Autonomic nervous system · Hypothalamus · Trigeminal-
autonomic reflex · Chronobiology
Introduction
The trigeminal autonomic cephalalgias (TACs) are a group
of primary headache disorders with core similarities.
The primary feature common to all is attacks of severe or
extreme, strictly unilateral headache of varying duration,
accompanied by cranial autonomic symptoms (CAS). The
group contains some of the most painful conditions known
to man—cluster headache (CH), paroxysmal hemicrania
(PH), short-lasting unilateral neuralgiform headache with
conjunctival injection and tearing (SUNCT), short-lasting
unilateral neuralgiform headache with cranial autonomic
features (SUNA), and hemicrania continua (HC)—all
classified according to the International Classification of
Headache Disorders (ICHD-3 beta) [1]. These disorders
are highly disabling, some with onset early in life and per-
sisting for many years, resulting in considerable economic
and social burden [2]. Although occasionally described as
rare, the prevalence of CH, the most prevalent of the TACs,
is 0.1%, comparable to Parkinson’s disease [3]. The TACs
share many clinical features; nevertheless, there are also key
differences, including treatment response, making clinical
differentiation crucially important. With their stereotypical
presentation, it may be surprising that a correct initial diag-
nosis is made in only 21% of CH patients, and the diagnostic
delay is 6 years [4, 5].
This review will give an overview of the clinical features
the pathology and how this affects clinical presentation and
treatment. The majority of our knowledge is centered on
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CH which is reflected in the following. Treatment will not
be covered in detail and readers are referred to exhaustive
reviews on this topic.
Search strategy
Relevant articles were identified by PubMed search using
the following terms: “trigeminal autonomic cephalalgias”,
“cluster headache”, “paroxysmal hemicrania”, “SUNCT”,
“SUNA”, “hemicrania continua”, “pathophysiology”, “head-
ache”. References of articles identified were also searched.
The searches were performed in May and June 2017. Only
English articles were included.
Clinical features
The primary differentiating features of the TACs are the
duration and frequency of attacks (Table 1). However, both
of these may overlap between disorders and clinically the
best method for reaching the correct diagnosis relies on a
detailed patient history as well as the use of a headache
diary. In some cases, and despite an overlap here also, treat-
ment response may aid the diagnostic process. There are no
known specific biomarkers for the TACs but imaging focus-
ing on pathology in the cavernous sinus and pituitary fossa
may be used to exclude secondary headache.
Besides the frequent, short-lasting attacks, the CAS
define these headaches and are part of the diagnostic criteria.
They result from parasympathetic hyper- and sympathetic
hypoactivity, and include conjunctival injection, lacrima-
tion, nasal congestion, rhinorrhea, eyelid edema, forehead
and facial sweating and/or flushing, a sensation of fullness
in the ear, miosis and ptosis. They are present to different
degrees, the most common being lacrimation, occurring in
around 75% of patients. Headache, CAS and the occasional
phono- and photophobia are completely lateralized [6]. The
attacks in CH, PH and SUNCT generally arise abruptly and
end just as abruptly, although pre-attack symptoms are prob-
ably under-recognized.
Cluster headache
Named for the tendency for attacks to cluster together at
specific times of the year, CH has the longest average attack
duration among the TACs, lasting around 45 min. Occurring
up to eight times a day, the pain is extreme, probably the
worst of all headaches, and biorhythmic features are highly
pronounced, with both circadian and circannual attack pat-
terns [7, 8]. Along with the CAS, most patients also experi-
ence restlessness or agitation during attacks. There are two
sub-diagnoses: (1) episodic (eCH; 80% of patients), where
attack periods lasting weeks or months are interspersed
with remission periods lasting longer than 1 month, and (2)
chronic (cCH; 20%), with no remission periods lasting more
than a month. Especially in eCH, attacks often occur during
sleep, and 80% of patients indicate that sleep or napping
triggers attacks [8].
CH treatment can be divided into three groups: abor-
tive, preventive and transitional/bridge therapy. Typically,
patients will use injectable or nasal triptans or oxygen

Table 1  Characteristics of the individual TACs Adapted from [100]

Cluster headache Paroxysmal hemicrania SUNCT Hemicrania continua

Attacks/day 1–8 1–40 3–200 Continuous

Attack duration 15–180 min 2–30 min 1–600 s Hours to days
Pain intensity Very severe Very severe Severe Varying with exacerbations
Typical pain location (Peri-)orbital, frontotemporal Frontotemporal, retro- Orbital, supraorbital, Temporal, periorbital
and periorbital temporal, trigeminal
Prevalence 0.1% 0.02–0.05% 0.05% Rare
Typical age of onset 20–40 20–70 35–65 35–50
Male/female 2.5/1 1/1 2/1 1/2.8
Restlessness 90% 80% 65% During exacerbations
Acute treatment response
 Oxygen 70% 0% 0% 0%
 Sumatriptan 90% 20% 0% Occasional
Preventive medications Verapamil Indomethacin Lamotrigine Indomethacin
Lithium
Indomethacin-responsive ± + – +
Rhythmic attack patterns + ± – –
Patients with spontaneous 80 20 Majority 15
remission periods (%)

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Clin Auton Res
delivered via a face mask at 8–15 L/min as abortive therapy
to end the attack [9]. While it has been suggested that oxy-
gen may be useful in migraine with CAS [10], it does seem
to be uniquely effective in CH and may be used in the dif-
ferential diagnosis.
First-choice preventive treatment is the calcium channel
blocker verapamil, administered with the aim of reducing the
duration, frequency and severity of attacks [9]. The method
of action of verapamil is unknown, but it is interesting that
this drug—as well as lithium, the second-choice preventive
therapy for CH—may show some efficacy in the treatment
of the chronobiological bipolar disorder [9, 11]. Topiramate,
methysergide, gabapentin and melatonin can be used in CH,
but are typically used only as third-choice preventives [9].
Oral glucocorticoids can be used as a transitional therapy,
administered for a rapid preventive effect, while verapamil or
lithium is being titrated [9]. If the side effects are tolerable,
glucocorticoids work very well in CH and some of the other
TACs [12]. Another option for transitional therapy is the
greater occipital nerve (GON) block using a local anesthetic
either alone or combined with injectable glucocorticoids.
Surgery is not widely used, due to inconsistent results and
adverse events. When it is used, the target is parasympathetic
or sensory pathways (gangliolysis, neurectomy, resection)
[13]. A more promising approach, however, is the use of
neurostimulation targeting the posterior hypothalamus, sphe-
nopalatine ganglion, occipital and vagal nerves, which has
demonstrated positive effects in a growing number of studies
conducted over the past two decades [14]. The effects of the
available modes of neurostimulation are not directly compa-
rable, since occipital nerve and deep brain stimulation seem
to have solely a preventive effect, whereas sphenopalatine
ganglion and vagal nerve stimulation have both acute and
preventive effects.
Paroxysmal hemicrania
PH may in some presentations resemble CH, the main differ-
ences being shorter, more frequent attacks and less predilec-
tion for nocturnal occurrence [15]. Oxygen is not effective,
possibly due to the shorter attacks and the somewhat delayed
onset of effect, but attacks can be completely prevented by
the non-steroidal anti-inflammatory drug indomethacin [16].
Using the same criteria as for CH, PH is classified as either
episodic (20–35%) or chronic (65–80%). It is not known
why most PH patients experience chronic symptoms while
most CH patients experience episodic events, and why PH
attacks do not show as marked a circadian rhythm. While
most attacks in PH arise spontaneously, it does appear that
10% are triggered mechanically, the C2–C3 region of the
neck being particularly sensitive. There appears to be no
preponderance by sex [17].
Given the high frequency of short attacks, therapeutic
focus should be on prevention. The first choice for PH is
indomethacin, typically in doses of 150–225  mg. [17].
Although the response is described as absolute, very high
doses of around 300 mg may be needed, and timing may
also play a role, some patients requiring 10 days of mainte-
nance therapy before any effect sets in, or needing to take the
medication at a specific time of day [18]. When the patient
is attack-free, tapering can be attempted at regular intervals,
and with the episodic subform, medication can be stopped
between attack periods. Gastroprotective measures should
always be considered, and not all patients can tolerate indo-
methacin in the doses required for efficacy; kidney function
may also need to be monitored. Other treatment options
include topiramate and GON blocks [19].
SUNCT/SUNA
SUNCT is characterized by still shorter and more frequent
attacks than PH. These are, per definition, accompanied
by conjunctival injection and lacrimation and last 1–600 s,
occurring with a very high frequency of up to 30 per hour
[20]. They can be triggered by mechanical stimuli to the
skin and can also occur as repetitive stabs [21]. In SUNA,
there may be any number of the previously described CAS.
The pain distribution is typically orbital or periorbital, and
the character can be electric or shock-like, hence the name
neuralgiform. Between attacks, most patients are completely
pain-free, and only seldom do attacks occur at night.
The concept of abortive therapy in a headache disorder
characterized by attacks whose duration is measured in
seconds is not realistic, and there are no controlled trials
investigating preventive treatment. Treatment is therefore a
specialist task, with evidence based on one large and several
small case series [22]. Preventive first-choice medication is
lamotrigine, with topiramate and gabapentin second. Extra
efficacy may be gained by combination with corticoster-
oids. However, as with all TACs, some cases are medically
refractory, and patients do not respond to or cannot tolerate
effective dosages. Magnetic resonance imaging may show
evidence of neurovascular compression in some patients,
and some of these may respond to microvascular decompres-
sion of the trigeminal nerve [23].
Although SUNCT and SUNA are classified as TACs, a
case has been made that these are more neuralgia-like and
should be classified as trigeminal neuralgia (TN) variants
[24]. This is supported by the finding of neurovascular com-
pression and the response to decompression. The ambiguity
is also underscored by the finding that in rare cases, TN
may be associated with CAS [25]. Unlike TN, however, in
SUNCT the majority of sufferers do not experience a refrac-
tory phase following attacks.
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Hemicrania continua
HC is likely very rare, with approximately 100 cases
reported, although the disorder may be underdiagnosed.
The pain is not as severe as with the other TACs—typically
mild to moderate—but it never remits completely, waxing
and waning throughout the day. There may be exacerbations
in the same sensory distribution of varying durations where
the pain is severe or very severe. As with the other TACs,
the pain is unilateral, and in contrast to migraine, the patient
may become restless and agitated during exacerbations
where CAS are also more pronounced. HC is more com-
monly found in women, and exists in two forms—remitting
and unremitting—with the latter being the most common.
The similarities between HC and migraine are the basis of
some discussion, and it was only in the most recent headache
classification that HC was placed together with the TACs
[26]. Like PH, HC responds absolutely to indomethacin
administered in a similar regime, with similar precautions.
Other treatments may include melatonin, GON blocks,
gabapentin and topiramate.
The natural course of HC is unpredictable. In the case
of freedom from pain under indomethacin, treatment taper-
ing can be tried after 2 weeks with absence of pain. If the
tapering is successful and the patient remains pain-free, all
scenarios can be encountered, including persisting remission
or future episodes of HC of varying durations [27].
Pathophysiology
While our understanding of the TACs remains imperfect,
there is strong proof that similarities extend from clinical
phenotype to pathophysiological mechanisms. In early years,
research efforts were focused on peripheral mechanisms.
This was motivated by observations such as the effective-
ness of glucocorticoids leading to suspicion that inflam-
mation, possibly in the cavernous sinus, could be involved,
but evidence of this was never found [28]. Vasodilation in
intracranial arteries and increases in particular neuropep-
tides measured in jugular blood are well-documented, but
are unspecific and are also seen in other circumstances, sug-
gesting that these phenomena are secondary in nature [29].
Lastly, the role of the trigeminal nerve in CH and PH may
in fact be secondary, since the pain is not always located
within the trigeminal distribution, and surgical resection of
this nerve does not always end the headaches, and when it
does, the effect may be temporary [13, 17, 30]. The fact that
provocation of cluster attacks using alcohol or nitroglycerine
is possible during, but not outside, the cluster periods seems
to suggest that the patient needs to be in a permissive state
for attacks to arise. Overall, peripheral mechanisms alone
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Clin Auton Res
cannot satisfactorily explain the complete symptomatology
of the TACs.
Involvement of areas of the pain matrix is not surprising
in a headache disorder, and was indeed found in neuroimag-
ing studies, but the discovery of specific hypothalamic acti-
vation during CH attacks, which was later demonstrated in
other TACs as well, cemented the concept of a strong central
component in the pathophysiology [31, 32]. Involvement of
central components is confirmed by the prominent chrono-
biological features and derangements of centrally regulated
hormones, as well as a close association with sleep in CH.
In the following sections, three major elements of TAC
pathophysiology will be covered: the trigeminal-autonomic
reflex, hypothalamic involvement, and sleep and systemic
autonomic changes.
The trigeminal‑autonomic reflex
CAS are not specific to the TACs, and can be seen in both
migraine and experimental pain in healthy volunteers [33,
34]. However, what is specific is how pronounced this cra-
nial autonomic activation is during attacks. The CAS result
from activation of the trigeminal-autonomic reflex, lead-
ing to increased cranial parasympathetic outflow [35]. The
afferent loop is made up of the trigeminal nerve, mostly
the first division, and activation of these fibers is likely
responsible for the pain. Sensory neurons in the trigeminal
ganglion innervate both extra- and intracranial structures
and meningeal vessels. Nociceptive signaling from these
reach the trigeminal nucleus caudalis (TNC; if the upper
cervical spinal levels are included, it is referred to as the
trigeminocervical complex). From here there are connec-
tions to brainstem, medullary, diencephalic, hypothalamic
and thalamic areas. Amongst these is a reflex connection to
the parasympathetic superior salivatory nucleus (SSN) in the
pons from which parasympathetic nerves arise [35]. These
autonomic fibers pass through the geniculate ganglion, syn-
apsing in the sphenopalatine ganglion, which gives rise to
innervation of the cranial vasculature by vasomotor neurons
and innervation of the lacrimal and nasal mucosa glands
by secretomotor neurons. While these circuits may explain
the increased parasympathetic tone during attacks, and can
account for the parasympathetic CAS, the miosis and ptosis
do not result from parasympathetic excess; rather, they result
from a sympathetic deficit. It is believed that these two CAS
may be caused by carotid wall swelling, compressing sym-
pathetic fibers projecting to the orbit.
Biomarkers for activation of the reflex have been iden-
tified: During CH and PH attacks, increases in calcitonin
gene-related peptide (CGRP) and vasoactive intestinal pep-
tide (VIP) can be measured in jugular blood on the attack
side, an indication of trigeminovascular and cranial para-
sympathetic activation, respectively [36, 37]. In humans,
Clin Auton Res
triptans and oxygen reduce the levels of both of these sign-
aling molecules [37], and the unique clinical usefulness
of oxygen in CH can probably be explained by a specific
inhibitory effect on the parasympathetic cranial outflow, in
turn inhibiting evoked trigeminovascular activation [38].
The triptans work on 5-HT(1B/1D) receptors, likely causing
presynaptic inhibition of cranial sensory nerves, although
central mechanisms have not been excluded [39, 40].
Invasive manipulation of the trigeminal-autonomic reflex
with interventions aimed at the sphenopalatine ganglion has
been practiced for almost 100 years, recently also including
local injection of onabotulinumtoxin A [41]. Interventions
also include neurostimulation targeting this ganglion. An
implanted device with stimulation electrodes in the spheno-
palatine fossa is activated and powered by remote control,
delivering on-demand stimulation. It has been shown to be
effective in around two-thirds of patients; initially investi-
gated as an abortive therapy, it appears to have a preven-
tive effect as well [42]. The device may work by breaking
the efferent loop of the trigeminal-autonomic reflex, lead-
ing to cessation of the ongoing attack, but elucidation of
mechanisms remain speculative. Research into pharmaco-
logical manipulation of trigeminal signaling is also a strong
field. Gepant-class CGRP receptor antagonists had shown
promising results in treating migraine attacks without the
vasoconstriction associated with the triptans [43]. However,
liver toxicity was an issue, and the drugs were discontinued.
Ditans (5-HT1F-directed agents) may offer similar advan-
tages and are being investigated [44]. Monoclonal antibodies
targeting CGRP and the CGRP receptors are currently being
explored in both migraine and CH, and initial results are
promising [45]. Manipulation of pituitary adenylate cyclase-
activating peptide-38 (PACAP-38) signaling also represents
a developing area in CH and headache therapy [46].
The above-described efforts over the past three decades
have shed light on these mechanisms, and we now have a
good understanding of the neurobiological substrate for
the pain and CAS. However, much remains unknown with
regard to the central mechanisms. What may complicate
matters is that CH and PH patients can experience attack
pain without autonomic features, and vice versa [17, 30, 47,
48]. Although this is a small minority, it still indicates that
pain and CAS are not inseparable and may not necessarily
be reflex-mediated. Further, while differential activation of
the trigeminal-autonomic reflex could explain the different
degrees of cranial autonomic activation seen in the TACs,
the reflex cannot be the sole component of the pathophysi-
ological mechanism. It does not explain the central effects
seen in some of the treatments or the absolute effect of
indomethacin in some TACs and complete ineffectiveness
in others, nor does it explain the chronobiological attack
patterns, hormonal changes, gender differences or efficacy
of deep brain stimulation. These observations introduce the
concept of hypothalamically modulated TAC reflex-based
syndromes.
Hypothalamic involvement
With a focus on CH, the case for hypothalamic involvement
rests on four lines of evidence: neuroimaging studies, effi-
cacy of deep brain stimulation, endocrinological changes
and chronobiological features (covered in the next sections).
Neuroimaging studies
Hypothalamic activation was first demonstrated in CH using
positron emission tomography (PET) functional neuroim-
aging [32]. These results were corroborated by findings of
increased cellular density in the same area and findings of
hypothalamic neuronal dysfunction as measured by mag-
netic resonance spectroscopy [49–51]. Patients with CH also
have decreased opioid receptor availability in the hypothala-
mus and anterior cingulate cortex that is dependent on dis-
ease duration [52]. Functional imaging studies in the other
TACs have also found activation of the posterior hypothala-
mus [53–56]. The pattern of hypothalamic activation seen
in the different TACs is not wholly the same, however, with
both ipsi- and contralateral as well as bilateral activation
observed. Furthermore, the stereotactic coordinates are not
completely identical between studies. Nevertheless, activa-
tion of part, or all, of the posterior hypothalamic area seems
certain.
The posterior hypothalamus connects to brainstem nuclei
including the SSN and TNC via direct, bidirectional connec-
tions referred to as the trigeminohypothalamic tract [57].
The descending connections, some of which are orexinergic,
are thought to regulate brainstem pain processing. Orexin
(hypocretin) is a hypothalamic neuropeptide involved in the
regulation of many homeostatic functions, including arousal
and pain processing, and injection of orexin B into the poste-
rior hypothalamus has been shown to increase spontaneous
firing in the TNC, increasing the response to dural stimula-
tion and noxious stimulation [58]. The response to orexin
A is the opposite—diminished trigeminal firing. Orexin A
levels in cerebrospinal fluid have been found to be depressed
in CH, but the immediate effect or cause of this remains
speculative [59]. Also, an association between CH and a pol-
ymorphism in an orexin receptor gene was found but was not
confirmed in a recent meta-analysis [60]. Orexins are most
famously involved in the regulation of the sleep–wake cycle,
as evidenced by the devastating result of complete deficiency
in the sleep disorder narcolepsy [61]. In CH, and perhaps the
TACs in general, this signaling system represents a possible
link between hypothalamic activation and descending noci-
ceptive modulation, sleep disturbances and chronobiological
features [62]. A dual orexin receptor antagonist, filorexant,
13

was recently investigated in migraine, where there was no
significant difference compared to placebo; however, selec-
tive antagonists and other forms of administration should
also be investigated [63].
Deep brain stimulation
In CH, PH and SUNCT, deep brain stimulation (DBS) tar-
geting the posterior hypothalamus has been used to treat
patients with chronic, medically refractory TAC, achieving
a response rate of around 60% [64]. PET functional neuro-
imaging has revealed increased blood flow in the ipsilateral,
posterior, hypothalamic gray matter and ipsilateral trigemi-
nal system in CH patients treated with DBS [65]. Several
theories for the effect have been proposed, including block-
ade of a local “cluster generator”, a non-specific antinocic-
eptive effect by activation of the periaqueductal gray and/or
rostral ventromedial medulla pain modulatory systems, and
finally, long-term modulation of neuronal pain-processing
pathways. Further research is necessary to elucidate this
effect.
Endocrinological changes
In CH, changes in several hormones have been observed,
including growth hormone, thyrotropin, gonadotropins,
testosterone, cortisol and melatonin [66]. Some of these
changes are present only during the cluster period, others
also during remission. However, considering the chronobio-
logical features, one of the most remarkable changes identi-
fied in CH patients is a lower level of melatonin and a blunt-
ing of nighttime increases [67]. Melatonin does have some
effect as a prophylactic or adjunctive therapy, especially
in eCH, and an association between daylight and cluster
occurrence has been identified [8]. Other endocrinological
Fig. 1  Different patterns of pain. Yellow boxes indicate typical tim-
ing of attacks in the trigeminal autonomic cephalalgias. eCH has
slightly fewer attacks than cCH, and these are more often associ-
ated with sleep. PH has more attacks which are less associated with
sleep. SUNCT has still more frequent and shorter attacks. The exac-
13
Clin Auton Res
changes include a lower level of testosterone, although this
may be secondary to reduced amounts of rapid eye move-
ment (REM) sleep [68, 69]. Still, it represents an interesting
finding, because, like the lower levels of opioid receptors, it
may contribute to an overall lowered pain threshold. Lastly,
and of particular clinical relevance, is the efficacy of gluco-
corticoids as a preventive and transitional therapy in several
primary headaches, but especially in CH [66]. Elucidation
of the mechanism behind its effect remains speculative,
but it has been suggested that it may work by normalizing
noradrenaline levels in the hypothalamus through complex
feedback mechanisms [66].
Chronobiology, sleep and systemic autonomic changes
The last—and perhaps most easily observed—evidence for
hypothalamic involvement in the TACs is the chronobiologi-
cal features inherent in CH. In the classical understanding
of headaches, focus was given to the pain, which of course
is the most debilitating and prominent symptom. However,
it is now apparent that this is only part of a larger complex
of symptoms and findings which result from dysregulation
of homeostasis.
The chronobiological patterns are most apparent in CH
where they have been studied in some detail. Here, attacks
commonly occur at night, typically arising 1–3 h after the
patient falls asleep (Fig. 1). This may be more pronounced
in eCH, and not so much in cCH. Concerning circannual
rhythms, some studies have found two peaks—typically
spring and autumn—although with some variation. A recent
study of Danish eCH and cCH patients found that cluster
occurrence was high from fall till spring and low during the
summer [8]. This is interesting in a setting of reduced mela-
tonin levels. It is also noteworthy that when going from the
episodic to the chronic phenotype of CH, and moving into
erbations in HC can vary greatly in duration. Cultural influences may
also affect attack timing. eCH episodic cluster headache, cCH chronic
cluster headache, PH paroxysmal hemicrania, SUNCT short-lasting
unilateral neuralgiform headache attacks with conjunctival injection
and tearing, HC hemicrania continua. Time is in 24-h format
Clin Auton Res
the TACs with more frequent attacks, it seems the associa-
tion with sleep is lost and attacks become more unpredict-
able. From a clinical standpoint, this naturally fluctuating
disease activity becomes a challenge when evaluating treat-
ment efficacy, as it will be difficult to assess whether a remis-
sion was due to a change in treatment or the cluster ending
of its own accord.
This close temporal connection between attacks and sleep
has prompted a number of studies (reviewed in [70]). Early
observations indicated that in eCH, attacks occurred during
REM sleep whereas this was not apparent in cCH [71]. More
recent and larger studies have not identified such a pattern
[68, 72]. However, there are indications that the attacks may
arise with the ending or start of sleep cycles, perhaps trig-
gered by shifts in autonomic tone. Overall, patients’ sleep is
fragmented, with a counterintuitive lower number of arous-
als compared to controls and lower REM density [68]. The
prevalence of sleep apnea may be higher in CH, although
this is not a universal finding, and there does not seem to be
any consistent improvement of the headache with successful
treatment of the apnea [68, 73].
In PH there are reports of single cases with completely
“REM-locked attacks” (17/18 attacks), but this has never
been confirmed in larger studies [74]. As stated previously,
SUNCT activity is reportedly not high at night, and noctur-
nal attacks should prompt suspicion of a symptomatic lesion.
In HC there are sparse reports that irregular sleep may trig-
ger exacerbations which may also occur during sleep, but no
other association has been reported.
Involvement of systemic autonomic regulation
There are multiple studies in the TACs showing that the
homeostasis of systemic autonomic regulation is affected.
This represents derangement separate from the described
CAS and is best characterized in CH [70], but is likely also
present in the other TACs. These are not necessarily subtle,
and indications of altered systemic autonomic function were
noted in the earliest accounts of the disorder [75]. They have
since been confirmed in a number of studies and include
bradycardia and cardioinhibitory syncope during attacks [76,
77]. This prompted the labeling of CH as a “parasympathetic
paroxysm”.
Several studies have found indications of systemically
increased parasympathetic tone including ECG changes
and bradycardia during spontaneous and provoked attacks
[78–82]. CH patients were also found to have abnormal
responses to standard autonomic tests such as deep breath-
ing, active standing, Valsalva maneuver and sustained hand-
grip [83–86]. A number of tilt-table studies have all found
altered autonomic and baroreflex function, with indications
of dysfunction in the parasympathetic division or in the
central relay from the baroreceptors, resulting in reduced
reactivity of the autonomic nervous system [87–92].
Past studies have shown that lesioning of the posterior
hypothalamus may result in a systemic sympathetic deficit,
whereas stimulation of this structure in CH increases the
sympathoexcitatory drive and improves sleep structure and
quality [90, 93, 94]. This observation again draws attention
to orexinergic signaling which is involved in the control of
the autonomic nervous system [95]. As stated previously,
orexin has been shown to be decreased in CH, and narco-
lepsy patients, completely deficient in orexin, have a reduced
sympathetic drive in wakefulness [96].
Other than the above-described instances of bradycar-
dia and syncope, there are no reports that these changes in
systemic autonomic regulation represent a frequent clinical
problem. However, how these findings relate to the obser-
vation that CH attacks have a propensity for arising during
times of increased parasympathetic tone may be relevant
with regard to patient education. It could be speculated that
the increased parasympathetic drive seen during attacks
could result from activation of the trigeminal-cardiac reflex;
however, this would not explain changes in sympathetic tone
or changes observed in the attack-free state [97]. The effi-
cacy of vagal nerve stimulation in some CH patients is also
an interesting finding in this regard. Possible mechanisms for
headache relief have been described, and stimulation of this
nerve has been noted to affect trigeminal nociception [98].
Conclusion
Despite the bulk of evidence in favor of a central role of
the hypothalamus, it remains unknown whether this brain
region triggers attacks, serves to end attacks or has a per-
missive role in allowing self-perpetuation of the trigeminal-
autonomic reflex. Further, whether the TACs really represent
individual clinical entities or are a continuum of differen-
tial manifestation of symptoms and epiphenomena remains
a debatable issue [99]. It is possible that in the setting of
reduced descending antinociceptive input to the brainstem,
the threshold for activation of the trigeminal autonomic
reflex is lowered and thus can activate and reactivate via
positive feedback, leading to the CAS and the pain. Such a
theory would explain the headache, the CAS and the accom-
panying features of the TACs; however, it does not explain
the differences between the TACs.
In a clinical setting, the primary focus must be the alle-
viation of pain by established treatment regimes. However,
an understanding of the seasonal and diurnal nature of the
TACs is imperative in patient education and timing of ther-
apeutic efforts. This has hitherto not been systematically
applied or investigated in the TACs, but with better knowl-
edge of how attack patterns manifest, this may change. In
13

the coming years, advances in animal models, neuroimaging,
neurostimulation and neuropharmacology are sure to deepen
our understanding of these disabling headache syndromes.
Compliance with ethical standards  17:327. doi:10.1007/s11916-013-0327-x
Conflict of interest  The author has been a speaker and consultant
for Autonomic Technologies, Inc. (ATI), for which he has received
honoraria.
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