603

Cluster Headache and Other Trigeminal

Autonomic Cephalalgias
Brian E. McGeeney, MD, MPH, MBA1

1 Department of Neurology, Boston University School of Medicine, Address for correspondence Brian E. McGeeney, MD, MPH, MBA,
Boston, Massachusetts Department of Neurology, Boston University School of Medicine,
Boston, MA (e-mail: bmcg@bu.edu).
Semin Neurol 2018;38:603–607.

Abstract The trigeminal autonomic cephalalgias are a group of distinct primary headache
disorders that share common characteristics of strict unilateral headache often
accompanied by unilateral cranial autonomic features. Cluster headache is the most
well-known example, but other than neurologists, practitioners often have limited
familiarity with these disorders and treatment options. Delays in diagnosis are typical
Keywords and treatment options remain suboptimal, associated with limited scientific research
► cluster headache

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into these brain disorders. Improved familiarity with core clinical features by health
► paroxysmal care providers should lead to earlier referral to specialists, and this education is the
hemicrania responsibility of headache medicine specialists. Optimistically, the last few years have
► trigeminal autonomic seen lobbying for more federal research support in headache medicine and there has
cephalalgia been renewed interest by private industry in potential new treatments for trigeminal
► hemicrania continua autonomic cephalalgias.

The trigeminal autonomic cephalalgias (TACs) represent a
collection of strictly unilateral primary headache disorders
commonly associated with unilateral cranial autonomic fea-
tures, separate from other primary headache diagnoses such as
migraine (►Table 1).1 Formerly the TACs included only short-
lived headache syndromes (cluster headache (CH), paroxysmal
hemicrania (PH), short-lasting unilateral neuralgiform head-
ache attacks [SUNHA]), but hemicrania continua (HC) has been
added into the TACs. Healthcare providers (apart from neurol-
ogists and headache specialists) often have poor familiarity
with the TACs, leading to delayed diagnosis and treatment. CH is
by far the most well-known member of the TACs. Experimental
and human functional imaging with multiple modalities links
the TACs with activation of the posterior hypothalamus,
although what role, if any, the hypothalamus plays in initiating
an attack is not known.2 The pathophysiological basis for the
TACs is still not well understood. Cranial autonomic features
(tearing, rhinorrhea, blocked nasal passages, sweating, and
flushing, among others) arise from a well-described trigem-
inal-autonomic reflex. Increased parasympathetic activity
derives from the superior salivatory nucleus in the pons,
whereupon fibers pass through the geniculate ganglion, synap-
sing in the sphenopalatine ganglion and from there innervating
the adjacent vasculature, lacrimal glands, and nasal mucosa.
Such autonomic features are not unique to TACs (occurring in
migraine and experimental pain), but their intensity, frequency,
and unilaterality aide in the diagnosis of TACs. Interestingly,
ptosis and miosis, which are commonly seen in TACs, do not
result from parasympathetic excess, but a sympathetic deficit.
Migraine occurs in the TAC population with typical fre-
quency and should be easily identified and separated by
patient and practitioner. Hence the term “cluster migraine,”
a phrase not used in the International Classification of Head-
ache Disorders (ICHD), is confusing and might falsely suggest
an attack of blended characteristics which does not occur.1 The
term “cluster migraine” is also used in error for CH presenting
in a less common demographic, such as young women.
The last iteration of the ICHD (3rd edition) added HC into
the TAC group due to clinical similarities (unilateral pain,
often unilateral autonomic features), absolute response to
indomethacin-like PH, and functional brain imaging findings
similar to the TACs (notably activation of the posterior
hypothalamic gray matter).1 Except HC, all TACs may present
as chronic or episodic variants. Workup of a TAC warrants an

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604 Cluster Headache and Other Trigeminal Autonomic Cephalalgias
Table 1 Characteristics of the different trigeminal autonomic cephalalgias
Characteristics Cluster
headache
Major forms Episodic or chronic
Attack duration 15–180 min
Frequency 1–8/d
of attacks
Male:Female ratio 2.5:1
Indomethacin Typically not
response
complete
FDA sanctioned Sumatriptan s.c. (abortive)
treatments Vagal nerve stimulator “gammaCore”
(abortive episodic CH only)
Abbreviations: CH, cluster headache; s.c., subcutaneous; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic
features; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival edema and tearing.
MRI of the brain to look for secondary causes. The medical
literature is replete with case reports of tumors (benign and
malignant), blood vessel disorders (aneurysms, dissection,
etc.), and inflammatory/infective conditions (sinusitis,
demyelination, etc.) that can mimic TACs.3 Pituitary adeno-
mas are overrepresented in the TAC population.4 The main
differential diagnoses of TACs include migraine, intracranial
lesions, trigeminal neuralgia (TN), cervicogenic headache,
hypnic headache (nighttime only, less severe, typically bilat-
eral), orbital pathology, dental pathology, and traumatic
trigeminal neuropathies. In particular, TN may be separated
from the TACs by the preponderance for the lower two
divisions of the trigeminal nerve in TN, absence of autonomic
features, and a refractory period for TN attacks.
Few controlled studies are available to guide treatment of
the TACs; hence, a lot of therapeutic choices are based on
expert opinion and published cases. Making the diagnosis
requires proper elicitation of discriminatory clinical features,
as TACs remain a clinical diagnosis. The primary goal for
healthcare providers who are not headache medicine spe-
cialists is to recognize key clinical features of TACs, prompt-
ing appropriate referral for expert counsel on diagnosis and
management.
Cluster Headache
The term “cluster headache” was named by Edward Charles
Kunkle in 1952, when he used the term while presenting 30
cases of periodic headache (with all the characteristic fea-
tures of CH).5 Previous terms for CH included erythroproso-
palgia, ciliary neuralgia, and periodic migrainous neuralgia,
among many others. It was much later before CH would be
identified as separate to migraine and not simply a variation
of migraine. The prevalence of CH is up to 1 per 1,000
population, which translates to over 300,000 people in the
United States who have had CH at some time in their life.6 As
Seminars in Neurology Vol. 38 No. 6/2018
McGeeney
Paroxysmal Short-lasting unilateral Hemicrania
hemicrania neuralgiform headache continua
attacks
Episodic SUNCT or SUNA and each
or chronic has episodic and
chronic varieties
2–30 min 1–600 s Continuous
1–40/d 5–200/d Exacerbations
hours to days
1:2 2:1 1:2.8
Yes by No Yes by definition
definition
None None None
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much as 25% of people only ever experience one bout of CH.
Attacks of CH are associated with synchronized abnormal-
ities in the trigeminovascular system, the autonomic system,
and the hypothalamus. Experimentally, nitroglycerin-trig-
gered CH attacks are associated with activation of the
ipsilateral posterior inferior hypothalamic gray, among other
areas.2 Posterior hypothalamic functional abnormalities
have been demonstrated in all the TACs. It is not known
whether triggering changes responsible for an attack first
start in the brain or peripheral nervous system.
Smoking is thought to be a risk factor for CH, and there is a
well-known male predominance. CH and especially the
chronic subset are associated with substantial psychiatric
comorbidity, such as depression and anxiety. A study by
Manzoni and colleagues7 of 808 consecutive CH patients
referred to a single clinic noted the age of onset of CH to be
before age 19 years in 21% of males and 27% of females, with a
male to female ratio of 2.6:1. Older studies suggest a greater
male predominance possibly because of underdiagnosis in
women. Onset of CH in the pediatric population is frequent,
behooving pediatric neurologists to be very familiar with CH
and treatment options.
Clinical Features
The core clinical feature of CH is a strictly one-sided severe
head pain, generally around the ophthalmic division of the
trigeminal nerve, lasting 15 to 180 minutes (►Table 2).
Attacks of CH are invariably severe (although intensity can
vary) unless influenced by medication. CH is so named for
the collection of weeks (or months) when the sufferer is
subject to repeated attacks (the cluster period), typically one
to eight attacks a day, separated by remission periods of
months to years. The attack must be differentiated from
nonpainful “shadow” sensations often present during a
cluster period. Failure to do so can result in erroneous
diagnoses. Cranial autonomic accompaniments occur in
 Cluster Headache and Other Trigeminal Autonomic Cephalalgias
Table 2 Diagnostic criteria for 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 min
(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 rhinorrhea
c. Eyelid edema
d. Forehead and facial sweating
e. Forehead and facial flushing
f. Miosis and/or ptosis
2. A sense of restlessness or agitation
D. Occurring with a frequency between 1 every
other day and 8 per day
E. Not better accounted for by another ICHD-3 diagnosis
Source: Adapted from the International Classification of Headache
Disorders, 3rd edition.1
90% or more of attacks, most typically unilateral tearing,
rhinorrhea, and nasal blockage on the side of the pain. Other
possible features include ptosis and restlessness which is in
contrast to the desire of migraineurs to keep still. Another
characteristic and discriminatory feature of CH is a prepon-
derance of nighttime attacks. Sufferers are often awoken
early in the night with an attack, and sleep is not possible
until cessation of the attack. Multiple night attacks are
common. The chronobiological pattern of attacks furthers
the hypothesis of hypothalamic involvement, another differ-
entiating feature compared with other headache disorders.
Cluster periods tend to be more common in spring and
autumn, but can occur at any time. CH is episodic for up to
90% of subjects, while chronic is defined as CH for a year
without remission or remission periods lasting less than
3 months (recently changed from 1 month). Chronic CH may
start de novo or develop from episodic CH, and can remit to
episodic again or disappear. Attacks of CH can be triggered by
alcohol, histamine, or nitroglycerine, but typical attacks of
CH have no identifiable trigger. Sometimes, lying flat can
trigger an attack, resulting in sleeping in upright posture. A
leading fear of those with episodic CH is transformation to
the chronic variety.
Treatment
Cluster headache has suffered from lack of effective treat-
ments, and available options are often not well utilized by
practitioners. Few randomized controlled trials (RTCs) exist
for CH; hence, treatment choices are often made from expert
consensus and case reports/series. Treatment of CH is either
focused on aborting ongoing attacks or prevention of attacks
(prophylaxis). Given the brevity of attacks, oral abortive
treatment is generally avoided. Oxygen was first demonstrated
McGeeney 605
useful in 1952 by Horton.8 In 2009, Cohen and colleagues in an
RTC demonstrated how 12 L/minute oxygen is superior to
room air in aborting CH attacks.9 High-flow oxygen (15 L/
minute via facemask for 15–20 minutes) and subcutaneous
sumatriptan have level A evidence and good consensus opinion
as best abortive options, although zolmitriptan nasal spray (5–
10 mg) is a good alternative backed by clinical evidence.10 The
Center for Medicare and Medicaid Services has never covered
oxygen for CH, despite much protest by professional and
patient organizations. There appears to be an unwarranted
reluctance of some practitioners to prescribe oxygen, possibly
due to unfamiliarity with CH, over-caution, and a lack of
appreciation on the extent of benefit for many people. Oxygen
toxicity concerns are often expressed, but that is not a concern
with brief high-flow oxygen in everyday use for CH. Other
abortive options include nasal lidocaine spray and less com-
monly nasal ketamine spray.
Verapamil is the most commonly used prophylactic agent
for CH, but receives only a level C recommendation, due to
paucity and quality of the clinical trials.10 Verapamil is com-
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monly used at doses between 360 and 560 mg/day, although
higher doses may be required. Some experts feel the use of
immediate-release verapamil is better than controlled-release
options. Side effects of verapamil importantly include heart
block, and ECG monitoring is commonly enacted. Constipation
is also commonly present with verapamil use. Lithium has
been demonstrated to reduce the frequency of CH attacks, but
requires periodic blood tests and other oversight. Topiramate
and other antiseizure medications are commonly tried, but
often fail to deliver meaningful benefit. Many CH patients lapse
on prophylactic treatment due to lack of efficacy and side
effects. Demonstration of reduced serum melatonin in those
with CH, and blunted normal night elevations prompted the
popular use of nightly melatonin as a treatment, although
clinical trials are conflicting on benefit.11 Indomethacin is not
expected to result in cessation of attacks but is sometimes
tried. At the time of this writing, two monoclonal antibodies
against calcitonin gene-related peptide are being evaluated for
treatment in CH.
Temporary respite from attacks is often achieved by
prednisone or dexamethasone, which ordinarily should not
be used for extended periods of time due to side effect
burden. The biggest concern would be avascular necrosis,
mostly in the hips leading to hip replacement. A course of
intravenous dihydroergotamine every 8 hours for six doses
commonly stop attacks, which may return on stopping the
treatment. Occipital nerve blockade with lidocaine and a
steroid have also been shown to help. Neuromodulatory
treatment options, both invasive (brain stimulation, implan-
table nerve stimulators) and noninvasive (transcutaneous
stimulators) have become available as an option to treat
CH.12 Deep brain stimulation for highly selected patients has
been shown to be effective, but carries potentially serious
risks. Recently, the Food and Drug Administration approved a
hand-held vagal nerve stimulator to treat acute attacks of CH
in those with episodic CH.13 The clinical trials did not show a
benefit in those with chronic CH, and outcomes in those with
episodic CH are expected to be modest.
Seminars in Neurology Vol. 38 No. 6/2018
606 Cluster Headache and Other Trigeminal Autonomic Cephalalgias
Interestingly, patient-initiated use of the classical psyche-
delic agents (serotonin agonists) periodically with apparent
benefit (ceasing CH attacks for weeks, not just reducing
frequency) has fostered interest in nonpsychedelic analo-
gues like bromo-LSD.14
Paroxysmal Hemicrania
Paroxysmal hemicrania can be thought of as having the
clinical features of CH with short attack length. Attacks of
PH last 2 to 30 minutes, typically accompanied by unilateral
cranial autonomic features. Attack frequency is expected to
be more than five times a day, with a mean of 7 to 13 attacks
per day, which is notably different from that of CH. PH is
considerably less common than CH, and current studies do
not allow a good estimate on incidence and prevalence.
Similar to CH, PH is a severe pain, and typically has an abrupt
onset and cessation. Contrary to CH, PH does not have a
preponderance for night attacks. Photophobia and phono-
phobia are common with PH, and unlike CH, PH responds
completely (by definition) to indomethacin. Occasionally,
neck movements are identified as a trigger for some PH
attacks. Sjaastad and Dale first described chronic paroxysmal
hemicrania (CPH) in 1974 (more comprehensively in 1976),
and CPH appeared in the first ICHD in 1988.15,16 The current
classification of PH identifies episodic and chronic forms
based on the presence or absence of a remission period
lasting at least 3 months. A case series of 84 patients in
1989 found a female:male ratio of 2.36:1, although other
studies suggest a distribution closer to even.17 Therapy is
focused on prophylaxis, as the attacks are brief. The use of
subcutaneous sumatriptan or high-flow oxygen is typically
ineffective for PH. By definition, complete response to indo-
methacin is required (25 mg orally TID at least) for a diag-
nosis of PH, although tolerability can be difficult. Patients
typically need to continue treatment for months before an
effective taper; hence, gastric protection is recommended at
the same time. Otherwise, a variety of medications are used
without good evidence, given the rarity of PH. In an open trial
of 10 PH subjects, half experienced a good response to
verapamil up to 360 mg/day.18
Short-Lasting Unilateral Neuralgiform
Headache Attacks
Short-lasting unilateral neuralgiform headache attacks
(SUNHA), a rare disorder, refers to very brief moderate or
severe intensity unilateral headaches lasting 1 to 600 sec-
onds, typically located around an eye, associated with uni-
lateral cranial autonomic features typical to TACs. The pain is
often described as sharp, shooting, or burning in character,
and occurs tens if not hundreds of times a day. Attacks are
spontaneous or provoked by eating or mechanical stimula-
tion of the face. The clinical picture was described first in
1989 associated with unilateral conjunctival injection and
tearing, leading to the acronym SUNCT.19 This rare group
(SUNHA) is now subdivided into those with conjunctival
injection and tearing (SUNCT) and those without (short
Seminars in Neurology Vol. 38 No. 6/2018
McGeeney
lasting unilateral neuralgiform headache attacks with cranial
autonomic features—SUNA). Individuals with SUNA express
other cranial autonomic features such as sweating or flush-
ing. Both SUNCT and SUNA generally result in significant
impairment. Lamotrigine is a first-line therapy, with suppor-
tive published cases; otherwise, a wide range of medications
have been tried for prophylaxis. Successful treatment is
challenging, with much room for future improvement. The
SUNHA disorder is separated from TN by their association
with cranial autonomic features, involvement primarily of
the ophthalmic division of trigeminal nerve, and lack of a
refractory period for the pain attacks.
Hemicrania Continua
The original description of HC involved two patients, a 63-
year-old woman and a 53-year-old man who developed
strictly unilateral headache, continuous from onset (for years)
and an absolute response to oral indomethacin at 25 mg TID.20
The male patient experienced unilateral tearing and forehead
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perspiration with pain exacerbations. The female patient
experienced “jabs and jolts” but no autonomic features. In
ICHD-3, the facial/forehead autonomic features expanded and
the ceiling dose of indomethacin increased to 225 mg daily.
The diagnostic expansion has been heavily criticized by
Sjaastad who originally described HC.21 An important feature
of HC is exacerbation of moderate to severe intensity (com-
monly when HC comes to medical attention), but most of the
time the pain is not severe and the subject can function
quite well. Identifying only the exacerbations and not the
continuous background headache often leads to misdiagnosis.
Complete response to indomethacin is a requirement for
diagnosis and should be followed by efforts to find the
minimum dose needed to allay side effects. Many other
medications have been tried for HC, including celecoxib daily
in those who cannot take indomethacin. There is a female
preponderance for HC of at least 3:1. Patients with apparent
HC but who do not respond completely to indomethacin are
identified in practice, leading to differing opinions on how to
diagnose such individuals. The options are HC variant (not in
ICHD), migraine, or even cervicogenic headache among other
considerations.
Conclusion
The classical TACs are unified by their short-lived unilateral
headache feature, often accompanied by unilateral cranial
autonomic findings. HC, characterized by unremitting unilat-
eral headache, has been added to the TACs due to shared
characteristics. CH is by far the most well-known of the
classical TACs, but despite this delayed diagnosis remains
common (due to practitioner unfamiliarity), resulting in sub-
standard treatment. Misdiagnosis with CH is more likely in
young women, for instance. The big challenges attributed to
TACs remain the late diagnosis, lack of treatment options, and
limited research into the pathophysiological underpinnings.
Improvements in our understanding of the physiology of TACs
should ultimately allow better treatments to emerge.
 Cluster Headache and Other Trigeminal Autonomic Cephalalgias
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