Brief Report

Cluster headache: When to worry?

Two case reports

Cephalalgia
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! International Headache Society 2016
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DOI: 10.1177/0333102416652094
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Matteo Bellamio1, Mariagiulia Anglani2, Federico Mainardi3,

Giorgio Zanchin1 and Ferdinando Maggioni1
Abstract
Background: The clinical criteria for cluster headache (CH) are included in Chapter 3 of the International Classification
of Headache Disorders, 3rd beta edition (ICHD-III). CH may sometimes be secondary to other pathologies.
Case reports: We report two patients in whom the clinical features of CH initially fulfilled the ICHD-III criteria, but
who later presented some radical modifications in headache natural history as a result of a secondary pathology. The first
case of CH was secondary to a pontine cavernous angioma and the second to a cerebral venous thrombosis.
Conclusion: We highlight the importance of clinical modifications of CH that could suggest clinical investigations should
be performed or repeated to exclude a secondary pathology in a previously diagnosed cluster headache. Some of the
pathological mechanisms of CH and brain lesions are discussed.
Keywords
Cluster headache, secondary cluster headache, cavernous angioma, cerebral venous thrombosis, multiple sclerosis,
cluster headache mechanism
Date received: 23 March 2016; revised: 18 April 2016; accepted: 21 April 2016

Introduction
Cluster headache (CH) is a rare type of headache and
usually occurs between the third and fth decades of
life in men who smoke and drink alcohol; there is
peak incidence for both sexes between 20 and 29
years of age (1). The clinical criteria of CH are
included in the International Classication of
Headache Disorders 3rd beta edition (ICHD-III) (2).
CH may also be a manifestation of other pathologies
but, at the beginning, symptoms may be indistinguishable from the primary form of headache. A review of
the literature identied 158 published cases of clusterlike headache (CLH) since 2008 (3). Many of these
papers reported only a temporal correlation with the
underlying disease and the symptoms did not satisfy
all the criteria, whereas others reported radical
changes in the frequency, intensity of pain, or in the
responsiveness to drugs. We present the cases of two
patients with CH. One case was secondary to a brainstem cavernous angioma and case was secondary to a
cerebral venous thrombosis (CVT). We discuss the
possible relation with multiple sclerosis (MS).
Written informed consent was obtained from both
patients.

Case reports
Case 1
A 71-year-old man with an unremarkable familial and
personal history developed severe pain in the left periorbital region at the age of 51 years. The pain was
constantly associated with lacrimation and conjunctival
injection, which lasted 1520 minutes, and preferentially recurred at 2 am with a frequency of one attack
every other day for two months every six months. A
diagnosis of episodic CH was made and he started
treatment with carbolithium in association with desimipramine with an initial benet. He was evaluated at our
1

Headache Centre, Department of Neurosciences, University of Padua,

Italy
2
Neuroradiology Unit, Department of Medicine, University of Padua, Italy
3
Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital,
Venice, Italy
Corresponding author:
Matteo Bellamio, Headache Centre, Department of Neurosciences,
University of Padua, Via Giustiniani 5, 35128 Padua, Italy.
Email: matteo.bellamio@gmail.com

2
headache centre at the age of 65 years, when a brain
magnetic resonance imaging (MRI) scan showed a
lesion in the left pontine area, compatible with a cavernous angioma. This was not considered to be related
to the episodic CH and no surgery was carried out. The
headaches improved on treatment with corticosteroids
and methysergide. After several pain-free months, the
patient discontinued the methysergide and the pain
returned with the same features. Sumatriptan and
high-ow oxygen inhalation (7 l/min) were not completely eective, so treatment with verapamil and prednisolone was successfully started. After three years he
abruptly developed a chronic CH that was not responsive to verapamil, sodium valproate or gabapentin. A
new brain MRI scan showed a slight enlargement of the
cavernous angioma (Figure 1(a)) and brain surgery was
performed (Figure 1(b)). Complete resolution of the
pain was present at a six-year follow-up examination.

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and 2 pm) for two weeks; the pain was accompanied by
ipsilateral conjuntival injection, lacrimation and rhinorrhoea. Three months later he reported a second period
of CH, initially with the same features, but, after a
week, the pain became more intense, pressing and localized all over his head and was associated with a transient, uctuating loss of visual. After a month of
persistent attacks, he presented to our emergency
department with fever, signs of meningeal irritation
and intracranial hypertension. During his recovery,
brain MRI was performed and showed non-specic
white matter lesions (Figure 2(a)) and a left external
jugular vein thrombosis climbing up to the distal portion of the sigmoid sinus (Figure 2(b)). His blood
results were normal, although a cerebral spinal uid
examination showed evidence of IgG oligoclonal
bands. Treatment with warfarin and acetazolamide
was successfully started and one year later he was still
pain-free.

Case 2
A 29-year-old man with a silent medical history presented with a rst episode of episodic CH characterized
by a right-sided pulsating pain localized in the frontoorbital and nasal regions, which lasted for two hours
and recurred twice a day at the same time (around 2 am

Discussion
The pathophysiology of CH is complex and still
unclear; there is evidence to suggest the involvement
of the trigemino-vascular system and central brain
areas, but evidence on the link between them is lacking.

Figure 1. Upper panel: pre-surgery brain MRI scan. (a), (b) Sagittal T1W, (c) axial T2W and (d) T1W images. The images show a
small lesion in left lateral pontine region, localized near, and superomedial to, the trigeminal nerve root entry zone. Lower panel: postsurgery brain MRI scan. (a), (b) Sagittal T1W, (c) axial T2W and (d) T1W showing the removal of a small (biopsy-proved) cavernous
angioma.

Bellamio et al.

Figure 2. (a) Brain MRI FLAIR sequences showing the alteration of white matter in the proximity of the corpus callosum and in the
left periventricular region. (b) Angiography MRI sequences showing, in the venous phase, thrombosis of the distal portion of the left
sigmoid sinus and the left external jugular (highlighted by the white arrow) and probable thrombosis of the proximal transverse
ipsilateral sinus.

The peripheral mechanism could explain CH related to

facial pathologies in the trigeminal innervation areas.
Lesions involving the ipsilateral trigeminal root support
the role of the trigemino-vascular system in the pathogenesis of pain; its stimulation seems to be the key to
the ignition of a process that successively involves the
hypothalamus as the synchronizing structure of pain
development. However, this peripheral pathway is not
enough to explain the pain of CH. Matharu and
Goadsby (4) reported a patient in whom sectioning of
the trigeminal roots did not solve the pain; surgery performed on the trigeminal nerve is not associated with
long-lasting benets (5). The activation of central brain
structures, in particular the hypothalamus, is conrmed
by CH secondary to hypothalamic-hypophyseal pathologies, by positron emission tomography studies and by
the ecacy of hypothalamic neuromodulator agents.
All the available data suggest an integrated hypothesis
that connects the two pathways, as noted by Van Vliet
et al. (6) and by some experimental clinical models
represented by CLH (3).

Cluster headache and cavernous angioma

In previous reports, CLH secondary to dierent vascular diseases has accounted for 31.6% of reported cases,
but none was related to cavernous angioma (3). We

found reports of patients who developed migraine secondary to lesions in the midbrain and raphe-magnus
nucleus, which stresses the importance of the brainstem
in the pathogenesis of migraine (7). In our patient,
the lesion mainly aected the root of the trigeminal
nerve in the pontine insertion point, but an involvement of the central and parasympathetic areas has
been to be considered in the pathogenesis of pain in
this patient.

Cluster headache and cerebral venous thrombosis

The manifestations of CVT depend on the aected
structure and the extent of venous thrombosis; it
could mimic other diseases. The pain probably results
from stimulation of the pain-sensitive large dural sinus
and the sensory innervation of the dura mater and its
vessels (the ophthalmic branch of the trigeminal nerve);
their irritation could activate the autonomic pathway
responsible for the pain syndromes that usually persist
until the normalization of venous ow (8). Depending
on the growth of the thrombosis, the onset of headache
is gradual, diuse and usually constant; there can be
also sudden or explosive onset headaches (as in thunderclap headaches or subarachnoid haemorrhages) (9)
or intermittently sharp headaches (as in migraine).
There are few reports of CLH associated with CVT

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and there is no unequivocal theory to explain the symptoms. The cavernous sinus has been suggested as a
pathophysiological locus. Orbital phlebograms
obtained during attacks demonstrated an inammatory
vasculitic process in the ipsilateral-superior ophthalmic
vein and in the cavernous sinus, which is probably due
to venous stasis that obliterates the venous outow
(10). CVT in the straight sinus could involve the hypothalamus, explaining the periodicity of CH, whereas in
superior sagittal sinus thrombosis an intracranial
hypertension syndrome may develop.

Cluster headache and multiple sclerosis

Headache is not generally secondary to MS and the
relationship is poorly understood; however, recent
data show that headache is more common in patients
with MS (about 50%) than in the general population
(11). We found few cases of CH related to MS (12)
and all patients presented demyelinating lesions in the
pons or in the brainstem. The autonomic signs associated with CH could be mediated by the same central
autonomic reexes involved in the pathogenesis of
MS. The demyelinating lesions might stimulate the
trigemino-vascular system through the trigeminal (or
cervical superior nerve) aerent bres, triggering the
process that leads to secondary CH. CH attacks as
clinical overture symptoms of MS have to be considered as an exceptional condition, but a growing
number of such cases have been described over the
last few years (12).

Conclusion
There are few reported cases of CH related to CVT and
even fewer of CH related to cavernous angioma. In
these two patients, we observed a course of headache
history that changed with an abrupt switch into forms
that no longer fullled the ICHD criteria and were
refractory to treatment. The cavernous angioma and
CVT seemed not to be initially involved in the CH
pain, but later became relevant to its pathogenesis
and maintenance. Therefore we considered a causal
connection between the CH and the presence of a midbrain cavernous angioma or an ongoing process of
CVT because the patients remained pain-free a long
time after the resolution of the underlying pathology.
We could not make a clear diagnosis of MS, but the
evidence of white matter demyelinating lesions on the
brain MRI scan and oligoclonal bands on cerebrospinal
uid analysis requires close radiological and clinical
follow-up.
Our experience allows some considerations about
the mechanism of CH because there was a correlation
between the lesions and CH pain in these two patients.
Any drastic change in the clinical features of CH suggests that clinical investigations should be performed or
repeated because the change could represent a red ag
for a secondary pathology. In addition to the involvement of the hypothalamus and trigemino-vascular
system, we also have to consider the brainstem (in particular the pons and midbrain) as a strategic area of
functional linkage between the peripheral and central
pathways of CH pain.

Clinical implications
. Cluster headache could be the manifestation of a secondary neurological pathology such as cavernous
angioma or cerebral venous thrombosis.
. Cluster-like headache helps to understand some mechanisms of cluster headache attack and can identify
some strategic brain areas.
. Variations in headache features (i.e. duration or response to treatment) suggest that clinical investigations
should be performed or repeated to exclude a secondary pathology in a previously diagnosed cluster
headache.

Declaration of conflicting interests

References

The authors declared no potential conicts of interest with

respect to the research, authorship, and/or publication of this
article.

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Funding
The authors received no nancial support for the research,
authorship, and/or publication of this article.

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